Summary
Background
Outcomes of older patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remain unsatisfactory. The primary objective of this trial was to establish whether decitabine combined with reduced-intensity conditioning (RIC) regimen could improve overall survival (OS) for this population in composite complete remission (CRc).
Methods
We conducted a single-arm, phase 2 trial at six hospitals in China. Eligible patients were aged 60–80 years, had a diagnosis of AML, achieved CRc at transplantation, were willing to undergo the first allo-HSCT, and had an Eastern Cooperative Oncology Group performance status of 0–2. Patients received decitabine combined with RIC regimen, comprising decitabine 20 mg/m2 daily intravenously (days −9 to −7), busulfan 3.2 mg/kg daily intravenously (days −5 to −4), and fludarabine 30 mg/m2 daily intravenously (days −6 to −3). The primary endpoint was 2-year OS rate. All efficacy and safety endpoints were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03530085) and is complete.
Findings
Between Jan 1, 2021 and Nov 30, 2022, 60 patients were enrolled. With a median follow-up of 35.5 months (IQR 32.5–39.2), 39 patients survived and 21 died. The 2-year OS rate was 67% (95% CI 56–80), which met the primary objective. Within 100 days post-transplantation, the most common grade 3–4 non-hematological treatment-emergent adverse events (TEAEs) were infections (22 [37%]), acute graft-versus-host disease (21 [35%]), and gastrointestinal disorders (16 [27%]). Five (8%) patients died of TEAEs, with one death treatment-related.
Interpretation
Decitabine combined with RIC regimen exhibits encouraging OS and acceptable toxicity profile, which might be a suitable therapeutic option for older patients with AML.
Funding
National Natural Science Foundation of China; Science and Technology Program of Guangdong Province; National Key Research and Development Program of China.
Keywords: Decitabine, Reduced-intensity conditioning, Older, Acute myeloid leukemia, Allogeneic hematopoietic stem cell transplantation
Research in context.
Evidence before this study
Outcomes post-transplantation in older patients with acute myeloid leukemia (AML) remain unsatisfactory, which justifies the attempts to seek new conditioning regimen for this patient population. We searched PubMed between database inception and Nov 30, 2024, to identify studies about conditioning regimens for allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in older patients with AML, with the terms (“older” OR “elderly”) AND “acute myeloid leukemia” AND “allogeneic transplantation” AND “conditioning regimen”, with no language restrictions. Before we designed this trial, multiple retrospective and prospective studies showed that myeloablative conditioning (MAC) regimens had lower relapse incidences but higher non-relapse mortality (NRM) than reduced-intensity conditioning (RIC) regimens in older patients with AML. Neither the MAC nor RIC regimens yielded satisfactory overall survival (OS). Preclinical studies demonstrated that hypomethylating agents such as decitabine (DAC) exerted synergistic anti-leukemic effects with alkylating agents such as busulfan (Bu). Several retrospective studies showed that the introduction of DAC to MAC regimen was effective and tolerable in younger patients with hematological malignancies. However, DAC combined with MAC regimen might not be suitable for older patients with AML due to the high NRM. At the time we designed our trial, no results had been reported from retrospective or prospective studies about DAC combined with RIC regimen in older patients with AML.
Added value of this study
We evaluated the efficacy and safety of DAC combined with Bu plus fludarabine (BuFlu) RIC regimen in older patients with AML. To our knowledge, this is the first prospective study investigating the efficacy and safety of DAC combined with RIC regimen in older patients with AML in composite complete remission (CRc) undergoing allo-HSCT. DAC combined with BuFlu RIC regimen is associated with encouraging OS and acceptable toxicity profile in these patients.
Implications of all the available evidence
The novel regimen of DAC combined with BuFlu RIC can improve survival by reducing relapse without increasing NRM in older patients with AML in CRc undergoing allo-HSCT. This strategy might be a suitable therapeutic option for this population.
Introduction
Acute myeloid leukemia (AML) is a hematological malignancy primarily affecting older individuals, with a median age of 68 years.1 Prognosis of older patients with AML is dismal, frequently attributed to the increased comorbidities, chemotherapeutic resistance, and adverse-risk genetics.2 Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potent curative approach for AML, but outcomes post-transplantation of older population remain unsatisfactory, with the 2-year overall survival (OS) rate of approximately 45%.3,4 Apart from patient-related and disease-related factors, the conditioning regimen is an essential factor affecting outcomes post-transplantation.5 Currently, the optimal conditioning for older patients with AML remains unclear. Myeloablative conditioning (MAC) regimens are associated with lower relapse incidences, but no improved survival is observed in older patients with AML due to the high non-relapse mortality (NRM).5,6 The development of reduced-intensity conditioning (RIC) regimens has decreased NRM and enhanced the feasibility of allo-HSCT in older patients with AML. Nonetheless, RIC regimens may not sufficiently control disease and thus result in disappointing relapse incidences.3,7 Therefore, seeking new conditioning regimens with both sufficient anti-leukemic effects and acceptable toxicity profile is crucial for the management of older patients with AML.
Hypomethylating agents (HMAs) such as decitabine (DAC) and azacitidine are recommended for the treatment in older and unfit patients with AML as a single agent or combination therapy.8 Preclinical studies demonstrated that DAC exerted synergistic anti-leukemic effects with DNA alkylating agents such as busulfan (Bu) in AML.9,10 In retrospective and prospective studies including our own, DAC was incorporated into the MAC regimen and contributed to favorable outcomes post-transplantation in younger patients with hematological malignancies.11, 12, 13, 14 However, a prospective study reported that DAC and venetoclax combined with MAC regimen did not improve survival in older patients with high-risk myeloid malignancies due to the high NRM.15 So far, there have been no retrospective and prospective studies investigating DAC combined with RIC regimen in older patients with AML. Based on these premises, we conducted a multicenter, single-arm, phase 2 trial to evaluate the efficacy and safety of DAC combined with RIC regimen in older patients with AML in composite complete remission (CRc) undergoing allo-HSCT.
Methods
Study design and participants
This single-arm, phase 2 trial was performed at six hospitals in China. Eligible patients were aged 60–80 years, had a diagnosis of AML, achieved CRc at transplantation, were willing to undergo the first allo-HSCT, and had an Eastern Cooperative Oncology Group performance status of 0–2.
The diagnosis of AML was based on criteria from the National Comprehensive Cancer Network. Cytogenetic analysis was performed by conventional chromosome banding and/or fluorescence in-situ hybridization. Molecular analysis was performed by polymerase chain reaction (PCR) and/or 173-gene next generation sequencing (platform, Next550Dx; average depth, 1500x; Appendix 2 p 1). Risk stratification was determined based on the European LeukemiaNet (ELN) 2017 criteria.16 CRc comprised complete remission (CR), CR with incomplete platelet recovery (CRp), and CR with incomplete hematological recovery (CRi). CR was defined as bone marrow blasts less than 5%, absence of circulating blasts and blasts with Auer rods, absence of extramedullary disease, and an absolute neutrophil count ≥1.0 × 109/L and a platelet count ≥100 × 109/L.16 CRp met all criteria for CR except that for platelets (platelets <100 × 109/L), and CRi met all criteria for complete remission except that for residual neutropenia (absolute neutrophil count <1.0 × 109/L), thrombocytopenia (platelets <100 × 109/L) or both.
Patients were excluded from the study if they had acute promyelocytic leukemia, uncontrolled infections, liver dysfunction (total bilirubin, alanine or aspartate aminotransferase ≥2 times the upper limit of normal [ULN]), renal dysfunction (creatinine ≥2 times the ULN or creatinine clearance rate <30 mL/min), severe cardiovascular disorders, severe pulmonary disorders (including respiratory failure characterized by PaO2 ≤ 60 mm Hg), or any disorder not suitable for the trial. Donor-specific anti-HLA antibodies (DSAs) were checked in all donors of haploidentical transplant. Haploidentical donor with a DSA mean fluorescence intensity >2000 was excluded in this trial.
Procedures
On the basis of our practice guidelines, an HLA-matched sibling donor (MSD) was the first choice, followed by an HLA-matched unrelated donor (MUD). If both donor types were unavailable, patients would receive a transplantation from an HLA-haploidentical donor (HID).
Patients received DAC combined with RIC regimen, comprising DAC 20 mg/m2 daily intravenously on days −9 to −7, Bu 3.2 mg/kg daily intravenously on days −5 to −4, and fludarabine (Flu) 30 mg/m2 daily intravenously on days −6 to −3. No dose reductions or interruptions were allowed.
Patients were withdrawn from the study if any intolerable adverse events (AEs) related to study treatment occurred, if the study was terminated, if the patient withdrew informed consent, or if any clinical AE or laboratory test result indicated that study treatment was not in the patient’s best interest. Patients could be withdrawn from the study at any time at the investigator’s discretion.
MSD or MUD recipients were transplanted with peripheral blood stem cell grafts, and HID recipients were transplanted with peripheral blood stem cell grafts combined with bone marrow.17 Cyclosporin A, methotrexate, mycophenolate and antithymocyte globulin (ATG; rabbit anti-human thymocyte immunoglobulin, ImtixSangstat, Lyon, France) were administered for graft-versus-host disease (GVHD) prophylaxis. The total dose of ATG was 2.5 mg/kg for MSD recipients, 7 mg/kg for MUD recipients, and 7.5 mg/kg for HID recipients in divided doses from days −3 to −1. Infection prophylaxis and supportive care were according to our previous description.17 Patients with FLT3-ITD mutations were to receive sorafenib as maintenance.
Bone marrow assessments were done before enrollment, every month for the first 3 months post-transplantation, every 2 months from the fourth to the nineth month post-transplantation, and then every 3 months until the study was completed. Measurable residual disease (MRD) was evaluated in all patients using eight-color multiparameter flow cytometry (MFC) with a threshold of 0.01%. MRD by quantitative PCR was also evaluated in a proportion of patients with RUNX1-RUNX1T1 and CBFβ-MYH11 with a threshold of 0.001%. Patients 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 Epstein–Barr virus (EBV) and cytomegalovirus (CMV) DNA loads in the peripheral blood were measured by quantitative real-time PCR weekly for the first 3 months post-transplantation, once every 2 weeks from the fourth month to the ninth month post-transplantation, once every month from the tenth month to the 12th month post-transplantation, and then once every 3 months until the study was completed. If peripheral blood tested positive for either virus, participants were monitored twice a week. The threshold for virus copies in plasma provided by the manufacturer (ZJ Bio-Tech, Shanghai, China) was fewer than 500 copies/mL. Physical examinations, laboratory tests including routine blood tests, blood biochemistry, urinalysis, electrocardiogram, and chest imaging examinations were done throughout the study.
RRT was assessed within 28 days post-transplantation and was graded according to Bearman’s criteria.18 AEs were recorded within 100 days post-transplantation according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, except for GVHD. Acute GVHD (aGVHD) and chronic GVHD (cGVHD) were graded according to established guidelines,19,20 and were categorized as AEs according to the following criteria.21 Grade I aGVHD without intervention was graded as grade 1 AE, grade I aGVHD with intervention as grade 2 AE, grade II aGVHD as grade 3 AE, grade III-IV aGVHD as grade 4 AE, and death due to aGVHD as grade 5 AE. With regards to cGVHD, mild cGVHD without systematic intervention was graded as grade 1 AE, mild cGVHD with systematic intervention as grade 2 AE, moderate cGVHD as grade 3 AE, severe cGVHD as grade 4 AE, and death due to cGVHD as grade 5 AE. Treatment-emergent AEs (TEAEs) were defined as any AE that was not present before (or worsening with) treatment.
Outcomes
The primary endpoint was 2-year OS rate. OS was defined as time from treatment until death from any cause. Secondary endpoints included 2-year disease-free survival (DFS) rate, 2-year cumulative incidence of relapse, 2-year cumulative incidence of NRM, median time to relapse, median time to engraftment, 28-day cumulative incidence of engraftment, 100-day cumulative incidence of aGVHD, 2-year cumulative incidence of cGVHD, and 2-year cumulative incidence of CMV/EBV infections. DFS was defined as time from treatment to relapse or death from any cause. Relapse was defined as either reappearance of leukemic blasts in the peripheral blood or at least 5% blasts in the bone marrow aspirate or biopsy specimen not attributable to any other cause, or reappearance or new appearance of extramedullary leukemia. NRM was defined as death from any cause not subsequent to relapse. Neutrophil engraftment was defined as the first of three consecutive days with absolute neutrophil counts exceeding 0.5 × 109/L without growth factor support. Platelet engraftment was defined as the first day of three consecutive platelet count measurements greater than 20 × 109/L without platelet transfusion for seven consecutive days.3
Sample size
This trial was designed to test the hypothesis that DAC combined with Bu plus Flu (BuFlu) RIC regimen was more effective than the previously reported MAC or RIC regimens at improving OS for older patients with AML in CRc. The sample size was calculated based on the primary endpoint, the 2-year OS rate, which was approximately 45% in this population receiving MAC or RIC regimens.3,4 To identify a 20% absolute increase in the 2-year OS rate with DAC combined with BuFlu RIC regimen, a minimum of 54 patients was required to provide the study with a one-sided significance level of 0.05 and a power of 90%. In consideration of a 10% dropout, the total sample size was 60 patients. The sample size calculation was performed using PASS software (version 15.0).
Statistical analysis
Statistical analysis was done in the intention-to-treat population. The intention-to-treat population was defined as all included patients, and was the basis for the analysis of efficacy and safety endpoints in this study. The cutoff date for statistical analysis was Nov 30, 2024. Descriptive analysis of patient characteristics included median and interquartile range (IQR) for continuous variables, and absolute and relative frequencies for categorical variables. OS and DFS were estimated using the Kaplan–Meier method. The 95% CIs for the 2-year OS and DFS rates were calculated using the Greenwood formula. The median follow-up time was calculated using the reverse Kaplan–Meier method. Cumulative incidences of relapse, NRM, engraftment, GVHD and CMV/EBV infections were calculated accounting for competing risks. Relapse was a competing risk for NRM and vice versa. Competing risk for engraftment was death without engraftment, competing risk for GVHD included death without GVHD and relapse, and competing risk for CMV/EBV infections included death without CMV/EBV infections and relapse. Time-to-event endpoints were censored at the time of last evaluation. The CI for overall TEAE was calculated using the Wilson Score Interval.
The OS in patients experiencing relapse, which was defined as time from the date of relapse to death or the last follow-up, was a post-hoc exploratory analysis. We did post-hoc subgroup analyses of OS, DFS, and relapse by ELN 2017 risk, sex, MRD status at transplantation, hematopoietic cell transplantation-comorbidity index (HCT-CI), TP53 status, and DNA methylation-related mutation status. The Cox proportional hazards model was used for the analysis of risk factors for OS and DFS. The test indicated that the proportional hazards assumptions held. The following variables known to influence the outcomes were included in the post-hoc multivariable analyses: ELN 2017 risk, MRD status at transplantation, and HCT-CI. All statistical tests were two-tailed with a significance level of 0.05 except for the superiority hypothesis.
An independent data monitoring committee, which was mainly composed of hematologists, monitored the trial regularly (once every 2 months) with a focus on issues relating to quality of trial, adherence to trial interventions, visit schedules, loss to follow-up and administrative and safety data. SPSS version 22.0 and R version 4.0.0 were used for data analysis. The main R packages were as follows: “binom”, “survival”, “survminer”, “tidycmprsk”, and “plyr”. The trial is registered with ClinicalTrials.gov (NCT03530085) and has been completed.
Ethics approval
The trial was first approved by Medical Ethics Committee of Nanfang Hospital of Southern Medical University, and the reference number for the ethics committee was NFEC-2018-043. Subsequently, the remaining five centers conducted ethical filing. The trial was reviewed and approved by the ethics committee review board at each participating center and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from the patients and donors before the initiation of the study (Appendix 2 p 6).
Role of the funding source
The funding source did not have any role in study design, data collection, data analysis, interpretation of the results, or writing of the report.
Results
Between Jan 1, 2021 and Nov 30, 2022, 65 patients were assessed for eligibility, and 60 of whom were enrolled and received DAC combined with BuFlu RIC regimen. No patients deviated from the protocol, and all the 60 patients were included in the efficacy and safety analysis (Fig. 1). The median age was 65 years (IQR 63–68). With respect to ELN 2017 risk, eight (13%), 17 (28%), and 35 (58%) patients were favorable-, intermediate-, and adverse-risk, respectively. Besides, 7 (12%) patients had TP53 mutation (Table 1). The genetic landscape with ≥10% occurrence is shown in Fig. 2. DNMT3A (19 [32%]) was the most frequently mutated gene, followed by TET2 (17 [28%]), NPM1 (15 [25%]), FLT3-ITD (14 [23%]), RUNX1 (13 [22%]), SRSF2 (12 [20%]) and IDH2 (12 [20%]).
Fig. 1.
Trial profile. No patients discontinued the conditioning regimen, no patients deviated from protocol, and no patients were lost to follow-up. DAC = Decitabine. BuFlu = busulfan plus fludarabine. RIC = reduced-intensity conditioning.
Table 1.
Patient and transplant characteristics (intention-to-treat population).
| Variable | Patients (n = 60) |
|---|---|
| Patient age, years | 65 (63–68) |
| Sex | |
| Female | 28 (47%) |
| Male | 32 (53%) |
| Ethnicity | |
| Asian | 60 (100%) |
| ELN 2017 risk | |
| Favorable | 8 (13%) |
| Intermediate | 17 (28%) |
| Adverse | 35 (58%) |
| TP53 status | |
| Mutation | 7 (12%) |
| Wild type | 53 (88%) |
| Initial induction regimens | |
| Anthracyclines plus cytarabine | 30 (50%) |
| Venetoclax plus HMA | 19 (32%) |
| DAC, cytarabine, aclarubicin, and granulocyte colony-stimulating factor | 11 (18%) |
| Consolidation regimens | |
| Cytarabine-based | 43 (72%) |
| Venetoclax-based | 17 (28%) |
| Pre-transplant exposure to HMAs | |
| Yes | 33 (55%) |
| No | 27 (45%) |
| Chemotherapy cycles before transplantation | 3 (3–4) |
| Cycles required to achieve CRc | |
| One | 45 (75%) |
| Two or more | 15 (25%) |
| CR status at transplantation | |
| ≥CR2 | 3 (5%) |
| CR1 | 57 (95%) |
| MRD at transplantation | |
| Positive | 19 (32%) |
| Negative | 41 (68%) |
| HCT-CI | |
| ≤2 | 44 (73%) |
| >2 | 16 (27%) |
| Donor type | |
| MSD | 19 (32%) |
| MUD | 1 (2%) |
| HID | 40 (67%) |
| CD34+ cells per graft, 106/kg | 6.5 (4.7–9.1) |
| Center | |
| Nanfang Hospital | 20 (33%) |
| Dongguan People’s Hospital | 12 (20%) |
| Peking University People’s Hospital | 10 (17%) |
| Hebei Yanda Lu Daopei Hospital | 8 (13%) |
| Seventh Affiliated Hospital of Sun Yat-Sen University | 6 (10%) |
| First People Hospital of Chenzhou | 4 (7%) |
Data are n (%) or median (IQR). Percentages might not total 100 because of rounding. ELN = European LeukemiaNet. HMAs = hypomethylating agents. DAC = decitabine. CRc = composite complete remission. CR = complete remission. CR1 = first complete remission. CR2 = second complete remission. MRD = measurable residual disease. HCT-CI = hematopoietic cell transplantation-comorbidity index. MSD = HLA-matched sibling donor. MUD = HLA-matched unrelated donor. HID = HLA-haploidentical donor.
Fig. 2.
Genetic landscape of all patients (mutation frequency ≥10%). ELN = European LeukemiaNet. MRD = measurable residual disease. HCT-CI = hematopoietic cell transplantation-comorbidity index.
Of the 60 patients enrolled, 30 patients received a regimen of anthracyclines (daunorubicin or idarubicin) plus cytarabine as initial induction chemotherapy. Other initial induction regimens included venetoclax plus HMA (n = 19), and DAC, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (n = 11). Forty-five patients achieved CRc after one cycle of induction chemotherapy, and the other 15 patients achieved CRc after two or more cycles of induction chemotherapy. Sixty patients received consolidation chemotherapy, including cytarabine-based regimens (n = 43), and venetoclax-based regimens (n = 17). MRD positivity at transplantation was observed in 19 (32%) patients. Sixteen (27%) patients had HCT-CI >2. Nineteen (32%) patients received transplantation from MSD, one (2%) from MUD, and 40 (67%) from HID (Table 1).
With a median follow-up of 35.5 months (IQR 32.5–39.2), 39 patients survived and 21 died. Causes of death were leukemia relapse (n = 10), infections (n = 9), acute left heart failure (n = 1), and thrombotic microangiopathy (n = 1). Infection sites and pathogens were as follows: six patients died of pulmonary infection (four bacterial, one bacterial and fungal, and one viral), two patients died of bloodstream infections (both bacterial), and one patient died of viral encephalitis. The study met its primary objective. The 2-year OS rate was 67% (95% CI 56–80) for all patients, and median OS was not reached. The 2-year DFS rate was 62% (95% CI 51–75), and median DFS was not reached. The 2-year cumulative incidence of relapse was 22% (95% CI 12–33). The 2-year cumulative incidence of NRM was 17% (95% CI 9–27; Fig. 3, Table 2).
Fig. 3.
Overall survival (a), disease-free survival, cumulative incidence of relapse and cumulative incidence of non-relapse mortality (b) for all patients. Overall survival (c), disease-free survival (d), cumulative incidence of relapse (e), and cumulative incidence of non-relapse mortality (f) based on ELN 2017 risk. The 2-year estimates (95% CI) since treatment are displayed. DFS = disease-free survival. NRM = non-relapse mortality. ELN = European LeukemiaNet.
Table 2.
Primary and secondary outcomes (intention-to-treat population).
| Outcomes | Patients |
|---|---|
| Primary outcome | |
| 2-year overall survival rate | 67% (56–80) |
| Secondary outcomes | |
| 2-year disease-free survival rate | 62% (51–75) |
| 2-year cumulative incidence of relapse | 22% (12–33) |
| 2-year cumulative incidence of non-relapse mortality | 17% (9–27) |
| Median time to relapse, months | 10.1 (3.4–17.4) |
| Median time to neutrophil engraftment, days | 12 (11–14) |
| Median time to platelet engraftment, days | 14 (12–18) |
| 28-day cumulative incidence of neutrophil engraftment | 98% (88–100) |
| 28-day cumulative incidence of platelet engraftment | 91% (80–96) |
| 100-day cumulative incidence of grade II-IV aGVHD | 33% (22–45) |
| 100-day cumulative incidence of grade III-IV aGVHD | 12% (5–21) |
| 2-year cumulative incidence of overall cGVHD | 40% (28–52) |
| 2-year cumulative incidence of extensive cGVHD | 13% (6–23) |
| 2-year cumulative incidence of CMV viremia | 55% (41–67) |
| 2-year cumulative incidence of CMV-associated diseases | 7% (2–15) |
| 2-year cumulative incidence of EBV viremia | 23% (14–35) |
| 2-year cumulative incidence of EBV-associated diseases | 3% (1–10) |
Data are point estimate (95% CI) or median (IQR). aGVHD = acute graft-versus-host disease. cGVHD = chronic graft-versus-host disease. CMV = cytomegalovirus. EBV = Epstein–Barr virus.
Fourteen patients experienced relapse, as a result of hematological relapse in 11 patients, extramedullary relapse in two patients, and hematological plus extramedullary relapse in one patient. The median time to relapse for patients who relapsed was 10.1 months (IQR 3.4–17.4) post-transplantation (Table 2). Of the 14 patients who relapsed, four (29%) patients abandoned treatments and 10 (71%) received salvage therapy. Among the 10 patients receiving salvage therapy, two patients received chemotherapy, and the other eight patients received chemotherapy and donor lymphocyte infusion. Eventually, four (40%) of 10 patients obtained CRc after salvage therapy. At the last follow-up, three patients survived and 11 died. The 2-year OS rate in patients experiencing relapse was 21% (95% CI 8–58).
All patients had neutrophil engraftment except for one who died of acute left heart failure. The median time to neutrophil engraftment and platelet engraftment was 12 days (IQR 11–14) and 14 days (12–18), respectively. The 28-day cumulative incidence of neutrophil engraftment was 98% (95% CI 88–100), and 28-day cumulative incidence of platelet engraftment was 91% (80–96; Table 2).
None of the patients required a dose reduction or discontinuation due to RRT. Ten (17%) of the 60 patients developed at least one type of grade 3 or 4 RRT within 28 days post-transplantation. The most common RRT was oral mucosa (37 [62%]). One (2%) patient died of cardiac toxicity within 28 days post-transplantation (Appendix 2 p 2). All (100%; 95% CI 94–100) of the 60 patients developed at least one type of non-hematological TEAEs within 100 days post-transplantation. At least one type of grade 3 or 4 non-hematological TEAEs was reported for 45 (75%) patients. The most common grade 3 and 4 non-hematological TEAEs were infections (22 [37%]), aGVHD (21 [35%]), and gastrointestinal disorders (16 [27%]). Five (8%) patients died of TEAEs within 100 days post-transplantation, including infections (n = 3), cardiac disorder (n = 1), and vascular disorder (n = 1). Except that one cardiac disorder was attributed to RRT, the remaining four deaths were not treatment-related (Table 3).
Table 3.
Treatment-emergent adverse events within 100 days post-transplantation in the safety population.
| TEAE | Grade 1–2 | Grade 3 | Grade 4 | Grade 5 |
|---|---|---|---|---|
| Any TEAE | 53 (88%) | 34 (57%) | 11 (18%) | 5 (8%) |
| Infections or infestationsa | 8 (13%) | 16 (27%) | 6 (10%) | 3 (5%) |
| Gastrointestinal disordersb | 31 (52%) | 15 (25%) | 1 (2%) | 0 |
| Hepatobiliary or pancreatic disordersb | 2 (3%) | 1 (2%) | 1 (2%) | 0 |
| Skin and subcutaneous tissue disordersb | 5 (8%) | 2 (3%) | 0 | 0 |
| Cardiac disorders | 9 (15%) | 3 (5%) | 0 | 1 (2%) |
| Respiratory, thoracic, and mediastinal disorders | 8 (13%) | 2 (3%) | 1 (2%) | 0 |
| Renal or genitourinary disorders | 12 (20%) | 2 (3%) | 1 (2%) | 0 |
| General disorders and administration site conditions | 23 (38%) | 2 (3%) | 0 | 0 |
| Metabolism and nutrition disorders | 11 (18%) | 3 (5%) | 1 (2%) | 0 |
| Abnormal blood chemistry results | 10 (17%) | 5 (8%) | 0 | 0 |
| Nervous system disorders | 9 (15%) | 1 (2%) | 1 (2%) | 0 |
| Musculoskeletal or soft tissue | 3 (5%) | 1 (2%) | 0 | 0 |
| Immune system disorders | 4 (7%) | 1 (2%) | 0 | 0 |
| Vascular disorders | 3 (5%) | 2 (3%) | 1 (2%) | 1 (2%) |
| aGVHD | 9 (15%) | 14 (23%) | 7 (12%) | 0 |
| Secondary malignancyc | 0 | 0 | 1 (2%) | 0 |
Data are n (%). Table shows grade 1–2 adverse events that occurred in more than 10% of patients and all grade 3, 4, and 5 adverse events, which were recorded from enrollment to 100 days after transplantation. TEAE = treatment-emergent adverse event. aGVHD = acute graft-versus-host disease.
Excluded the patients with cytomegalovirus viremia and Epstein–Barr virus viremia.
Excluded the patients with GVHD.
Secondary malignancy was post-transplantation lymphoproliferative disease.
The 100-day cumulative incidence of grade II-IV aGVHD was 33% (95% CI 22–45) in the entire cohort, along with 16% (4–36) in the MSD group and 42% (26–56) in the HID group, respectively. The 100-day cumulative incidence of grade III-IV aGVHD was 12% (95% CI 5–21) in total. The 2-year cumulative incidence of overall cGVHD was 40% (95% CI 28–52), and extensive cGVHD was 13% (6–23). The cumulative incidences of grade III-IV aGVHD, overall cGVHD, extensive cGVHD were similar between the MSD and HID groups (Appendix 2 p 3). One patient in the MUD group had neither aGVHD nor cGVHD. The 2-year cumulative incidences of CMV viremia and CMV-associated diseases were 55% (95% CI 41–67) and 7% (2–15), respectively. The 2-year cumulative incidences of EBV viremia and EBV-associated diseases were 23% (95% CI 14–35) and 3% (1–10), respectively (Table 2).
The outcomes post-transplantation stratified by ELN 2017 risk are shown in Fig. 3. The 2-year OS rate was 75% (95% CI 50–100), 71% (52–96) and 63% (49–81), and DFS rate was 75% (50–100), 65% (46–92) and 57% (43–76) in the favorable, intermediate and adverse ELN risk groups, respectively. The 2-year cumulative incidence of relapse was 13% (95% CI 1–45), 18% (4–39) and 26% (13–41), and corresponding cumulative incidence of NRM was 13% (1–45), 18% (4–39) and 17% (7–31) in the favorable, intermediate and adverse ELN risk groups, respectively. The outcomes post-transplantation in other selected subgroups are shown in Appendix 2 p 4. The 2-year OS rate was 71% (95% CI 45–100), 66% (54–80) and 61% (45–82), DFS rate was 71% (45–100), 66% (54–80) and 57% (41–79), and cumulative incidence of relapse was 43% (8–76), 19% (10–31), and 21% (8–38) in patients with TP53 mutation, TP53 wildtype patients, and other patients in the adverse risk, respectively. Furthermore, at 2 years, the OS and DFS rates, and the relapse incidence were 73% (95 CI% 61–88), 73% (61–88), and 15% (6–27) in patients with DNA methylation-related mutations, compared with 53% (34–81), 37% (20–66), and 37% (16–58) in patients without DNA methylation-related mutations.
Post-hoc multivariable Cox analysis for OS showed that when the 3 factors (ELN 2017 risk, MRD status at transplantation, and HCT-CI) were considered together, HCT-CI >2 was associated with a higher risk of death (hazard ratio [HR] 3.00, 95% CI 1.23–7.33), whereas for DFS endpoint, MRD status at transplantation (HR 2.76, 95% CI 329 1.06–7.17) and HCT-CI (HR 2.73, 95% CI 1.18–6.31) were the strongest prognostic factors (Appendix 2 p 5).
Discussion
This phase 2 trial shows that DAC combined with BuFlu RIC regimen contributes to a low 2-year cumulative incidence of relapse of 22%. Additionally, the conditioning regimen is well tolerated, with the 2-year cumulative incidence of NRM of 17%. These effects further translate into an encouraging 2-year OS rate of 67% in older patients with AML. The observed survival result is compatible with the originally anticipated 2-year OS rate of 65%, suggesting the possible benefit of DAC combined with BuFlu RIC regimen for older patients with AML.
To date, there has been no specific recommendation on the optimal conditioning regimen for older patients with AML. Limited by either high NRM or relapse, neither conventional MAC nor RIC regimens benefit older patients in AML, with the 2-year OS rate of about 45% in this population,3,4 which is worse than that observed in younger patients.22 To improve outcomes post-transplantation in older patients with AML, in recent years, some attempts have been made by introducing targeted agents such as DAC and venetoclax to the conventional conditioning.15,23 Zheng et al. reported that DAC and venetoclax combined with MAC regimen resulted in a 1-year OS rate of about 55% in 19 older patients with high-risk myeloid malignancies.15 Garcia et al. reported that venetoclax combined with RIC regimen was feasible and safe for 22 patients with high-risk myeloid malignancies, of whom the majority were aged ≥60 years, with the 1-year progression-free survival rate of 53%.23 Recently, Lübbert et al. reported an international, multicenter, randomized, controlled, phase 3 trial about 606 older patients with AML randomly assigned to receive DAC or standard chemotherapy, of whom 199 patients underwent transplantation in CR/CRi with various RIC regimens. The results suggested that the 2-year OS rate post-transplantation was approximately 60%,24 which seemed similar to our survival result. It could not be excluded that the center effect, post-transplant treatments, and the heterogeneity of RIC regimens in Lübbert’s study might have influenced the survival comparison. In this trial, we employed DAC combined with BuFlu RIC regimen in older patients with AML, with the 2-year OS rate of 67%. Our result compared favorably with previous studies of both MAC and RIC regimens in older patients with AML,3,4 although cross-trial comparisons should be made with caution.
Relapse and NRM are major impediments to transplantation, especially for older patients with AML. For older patients receiving MAC and RIC regimens, the 2-year cumulative incidence of relapse was reported to be 24–35% and 30–44%, and the 2-year cumulative incidence of NRM was reported to be 24–32% and 15–26%, respectively.3,5, 6, 7 Some studies have suggested that targeted agents combined with MAC regimen may reduce relapse in younger patients.11, 12, 13, 14 Nonetheless, this conditioning strategy might be not suitable for older patients because of the high NRM.15 In this trial, DAC combined with BuFlu RIC regimen was used in older patients with AML. Our results indicated that compared with historical experience of MAC regimens,5,6 DAC combined with BuFlu RIC regimen could reduce NRM without increasing relapse. Meanwhile, compared with previous reports of RIC regimens,3,7 DAC combined with BuFlu RIC regimen might reduce relapse without increasing NRM. Reasonable explanations for the favorable outcomes might be that DAC enhanced the cytotoxicity of DNA alkylation agents, and the synergistic anti-leukemia effects mitigated relapse risk; meantime, the combination of DAC and BuFlu RIC did not increase NRM, both of which resulted in survival benefit ultimately.
Infection and GVHD are two main causes of NRM. In this trial, our results demonstrated that the toxicity profile of DAC combined with BuFlu RIC regimen was acceptable. The most common RRT was oral mucosa, and one (2%) patient died of cardiac toxicity within 28 days post-transplantation. Grade 3–4 non-hematological TEAEs were mainly infections, aGVHD, and gastrointestinal disorders. The results were similar to previous report of RIC regimens,3 underscoring the feasibility and safety of DAC combined with BuFlu RIC regimen in older patients with AML. Moreover, our results indicated that the incidences of II-IV aGVHD and overall cGVHD for the entire cohort were slightly lower than previous publication, in which the incidences of II-IV aGVHD and overall cGVHD were about 38% and 50% in older patients with AML.25 Notably, the corresponding incidences in the MSD group was remarkably lower than previous report.26 The incorporation of ATG into GVHD prophylaxis for all patients, especially for patients transplanted from MSD, might contribute to the lower incidences of GVHD, which was concordant with previous literature that the addition of ATG decreased the incidence of GVHD.27
Baseline concomitant genetics is a crucial predictor of outcomes post-transplantation. Some studies have revealed the correlations between genetics and outcomes post-transplantation in older patients with AML.28,29 Murdock et al. evaluated the impact of diagnostic genetics on outcomes post-transplantation in 295 older patients with AML, and found that TP53, FLT3-ITD without concomitant NPM1, KRAS, and JAK2 mutations were linked to inferior leukemia-free survival.28 Tsai et al. reported that AML patients with myelodysplasia-related mutations had statistically significantly poorer outcomes regardless of age, and allo-HSCT might ameliorate the negative impact of myelodysplasia-related mutations.29 In this study, exploratory analyses showed similar survival in all ELN risk, and TP53 status subgroups. These results might be attributed to the small number of patients in the ELN risk and TP53 status subgroups, and needed to be further investigated in large-sample clinical studies. Besides, our results suggested that older patients with DNA methylation-related mutations had favorable survival and relapse post-transplantation, which were similar to previous reports.30,31
Our study had several limitations that should be taken into consideration. First, it was a single-arm phase 2 trial, and the comparative data was limited to historical data and other published studies, which had an inherent risk of selection bias and difficulties in comparison with patients from other studies. The results were required to be validated in randomized controlled trials. Second, the results of post-hoc analyses were exploratory, and should be to be further verified in well-designed trials. Meanwhile, the relatively small sample size in subgroups might result in low test power. Third, although the median follow-up time was 35.5 months, a long-term follow-up is warranted to further evaluate the outcomes. Finally, although DAC combined with RIC regimen yielded a 2-year cumulative incidence of relapse of 22%, the relapse result was not completely satisfactory. As mentioned before, the conditioning containing venetoclax has shown promising efficacy in older patients with myeloid malignancies.15,23 To further improve the DFS, a new randomized controlled trial to compare the efficacy and safety of venetoclax, DAC, and BuFlu RIC with BuFlu RIC in older patients with myeloid malignancies is underway (NCT07052422).
In conclusion, our study suggests that the novel regimen of DAC combined with BuFlu RIC is effective and well-tolerated for older patients with AML in CRc undergoing allo-HSCT, which might be a suitable therapeutic option for this population. This study can provide the basis for future randomized comparisons to help confirm the benefit.
Contributors
LX, YW and QFL designed the study. LX, QFL, YW, ZLH, NX, and YRJ wrote the manuscript, collected the data and did the statistical analysis. QFL, YRJ, YXZ, HH, PZ and YW led the trial within each institute. All authors contributed to patient registration and treatment, provided clinical data, reviewed and approved the final draft. LX, YW and QFL accessed and verified all the data in the study. LX had full access to all the data in the study and all authors had final responsibility for the decision to submit for publication.
Data sharing statement
De-identified individual participant data that underlie the results reported in this Article and the protocol will be made available beginning 9 months and ending 36 months following article publication. Data will be made available to investigators whose proposed use of the data has been approved. Requests for data should be made by contacting the corresponding author (356135708@qq.com), and will be assessed by an independent review committee on a case-by-case basis. After 36 months the data and protocol will be available in our university’s data repository but without investigator support other than deposited metadata.
Declaration of interests
We declare no competing interests.
Acknowledgements
QFL was supported by the National Natural Science Foundation of China (82293634), and the Science and Technology Program of Guangdong Province (2023B110007). LX was supported by the National Natural Science Foundation of China (82170213, 82370216), and the National Key Research and Development Program of China (2021YFC2500300-4). RL was supported by the National Natural Science Foundation of China (82070190). We are grateful to all the patients and their families who participated in our clinical trial. We thank the members of the IDMC for their contributions: Prof Qianwei Liu, Prof Xiuli Wu, and Prof Yiwen Ling. We also thank Dr Huiwen Xue for the statistical analysis support.
Footnotes
Translation: For the Chinese translation of the abstract see the Supplementary Materials section.
Supplementary data related to this article can be found at https://doi.org/10.1016/j.lanwpc.2025.101664.
Appendix A. Supplementary data
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