A novel and safe protocol for patients with severe comorbidity who undergo haploidentical hematopoietic stem cell transplantation: A single-center prospective study
-
Wei Sun
Abstract
Background and Objectives
Haploidentical stem cell transplantation (haplo-HSCT) has demonstrated promising results in patients without severe comorbidities. There is also an increasing need for haplo-HSCT in patients with severe comorbidities. However, the high risk of treatment-related mortality (TRM) hindered its extensive application. We aimed to investigate a novel conditioning regimen (Bu/Flu/Cy/ATG) followed by haplo-HSCT in patients with severe comorbidities.
Methods
This prospective, single-arm clinical trial was performed at Peking University Institute of Hematology, China. Patients were enrolled if they were (1) diagnosed with acute leukemia, myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML); (2) patients with no HLA-matched sibling donor or matched unrelated donor available but with a haplo-HSCT donor; (3) patients with hematopoietic cell transplantation comorbidity index (HCT-CI) scores ≥3. The primary endpoint was 2-year TRM.
Results
From June 2018 to November 2022, a total of 72 patients were enrolled. All patients achieved neutrophil engraftment. The cumulative incidence of grade II–IV acute graft-versus-host disease (aGVHD) at day 100 was 20.8%. The cumulative incidences of cytomegalovirus (CMV) viremia and Epstein‒Barr (EB) viremia at day 100 were 72.2% and 31.9%, respectively. The cumulative incidence of 2-year TRM was 25.1%. The cumulative incidence of 2-year relapse was 8.6%. The probabilities of 2-year overall survival and leukemia-free survival were 71.9% and 65.6%, respectively.
Conclusion
This study suggested that a novel conditioning regimen followed by haploidentical HSCT might be a promising option for patients with severe comorbidities. The study was registered as a clinical trial (NCT03412409).
Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment option for hematologic malignancies. When matched sibling donors (MSDs) or unrelated donors (URDs) are not available, haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a viable and popular option that has been increasingly utilized in recent years. It has been demonstrated that haplo-HSCT can achieve similar or superior clinical outcomes compared to MSD or URD allo-HSCT.[1,2] It is remarkable that most patients who received haplo-HSCT in the early days were young patients or patients without severe comorbidities due to the concern that patients with comorbidities or older age have a higher risk of treatment-related mortality (TRM) post-hematopoietic stem cell transplantation (HSCT).[3,4] In fact, there is an unmet need for transplantation for this population.
The major concern of this latter population is increased transplant-related toxicity. The ways to address high TRM in these patients include optimizing conditioning regimens, reducing graft-versus-host disease (GVHD), and preventing and treating infections. The current research mainly focuses on improving conditioning regimens. In classical busulfan (Bu) /cyclophosphamide (Cy) conditioning, Cy is considered one of the most significant agents related to regimen-related toxicity.[5] Fludarabine (Flu) has been widely used to reduce regimen-related toxicity by replacing Cy with Flu.[6,7] A study from Peking University demonstrated that in patients with severe comorbidities, a modified Bu/Flu regimen was well tolerated and safe for use with human leukocyte antigen (HLA)-identical sibling transplantation.[8] Sung-Eun Lee et al. analyzed patients with old age and/or co-morbidities who received HLA-identical allo-HSCT with Flu/Bu/ total body irradiation (TBI) 400 cGy conditioning regimen. The estimated 2-year rates of overall survival (OS), event-free survival, transplantation-related mortality, and relapse were 66%, 63%, 26%, and 16%,[9] suggesting that this conditioning regimen may be a feasible therapeutic approach for acute myeloid leukemia (AML) with old age and/or co-morbidities. So far, there are no studies aiming at reducing TRM in patients with comorbidities who received haplo-HSCT. In a prospective single-arm phase 2 study conducted by our team, a novel conditioning regimen Bu/Flu/Cy/anti-thymocyte globulin (ATG) followed by haplo-HSCT was safe and feasible in older patients.[10] There is currently no data available on whether this conditioning regimen is safe and will reduce TRM in patients with hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥ 3. In this prospective, single-arm, observational clinical study, we aimed to explore the efficacy and safety of this novel Bu/Cy/Flu/ATG conditioning regimen in patients with comorbidities.
Methods
Patient enrollment
This single-arm prospective study was performed at the Peking University People’s Hospital, China. The inclusion criteria were as follows: (1) patients diagnosed with acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML); (2) patients with no HLA-MSD or matched URD available but with a haplo-HSCT donor; (3) patients with HCT-CI scores ≥3 but eligible for transplantation after being evaluated by a physician; and (4) patients who signed their informed consent. The exclusion criteria were (1) pregnancy; (2) active infection without control; (3) enrollment in other clinical trials within 1 month; (4) other contradictions to HSCT; and (5) no informed consent. This study was approved by the Ethics Committee of Peking University People’s Hospital. All patients provided written informed consent before enrollment. The study was registered as a clinical trial (ClinicalTrials. gov: NCT03412409).
Pretransplant comorbidities assessment
Comorbidities were assessed by a comprehensive review according to the HCT-CI classification.[11] Patients with HCT-CI scores ≥ 3 were selected based on the results of these assessments.
Transplant Regimens
Donor selection and HLA typing were previously described in detail.[12] The preconditioning regimen consisted of cytarabine (2 g/m2/day, -10 to -9 days), Bu (3.2 mg/kg/day, -8 to -6 days), Flu (30 mg/m2/day, -6 to -2 days), Cy (1.0 g/m2/day, -5 to -4 days), semustine (250 mg/m2, -3 days), and rabbit ATG (2.5 mg/kg, -5 to -2 days; Sanofi, France). All recipients received granulocyte colony-stimulating factor (G-CSF)-mobilized bone marrow and/or peripheral blood-derived stem cells. All patients received cyclosporine A, mycophenolate mofetil, and short-term methotrexate for GVHD prophylaxis.[13, 14, 15] Prophylaxis and treatment of cytomegalovirus (CMV) infection after haplo-HSCT were performed as described previously.[16,17] Ganciclovir was administered during conditioning (through day-2) and acyclovir (400 mg twice a day) was given until the discontinuation of all immunosuppressive agents. Due to its launch in China in August 2022, patients receiving haplo-HSCT after August 2022 were treated with letermovir for CMV prophylaxis. Patients also received prophylactic posaconazole to prevent infection by fungi.
Endpoints and definitions
The primary endpoint was the 2-year TRM. The secondary endpoints were regimen-related toxicity, engraftment, acute graft-versus-host disease (aGVHD), CMV reactivation, Epstein-Barr virus (EBV) reactivation, relapse, OS, and leukemia-free survival (LFS). According to the design of this study, regimen-related toxicity, engraftment, aGVHD, CMV reactivation, and EBV reactivation were the safety evaluation indicators.
Myeloid engraftment was defined as the first day of an absolute neutrophil count (ANC) of 0.5 × 109/L or more for three consecutive days, and platelet engraftment was defined as the first day of a platelet count of 20 × 109/L or more for seven consecutive days without transfusion. aGVHD was graded according to the modified Glucksberg criteria[18] and the National Institutes of Health (NIH) classification.[19] CMV and EBV viremia were defined as the first of two consecutive detections in which virus DNA reached or exceeded 1000 copies/mL and 500 copies/ mL, respectively. Relapse was defined as the reappearance of blasts in the blood, bone marrow (BM, > 5%) or any extramedullary site after complete remission (CR). TRM was defined as death after HSCT without disease progression or relapse. LFS was defined as the time from transplantation to relapse, disease progression, or death, whichever occurred first. OS was defined as the time from transplantation to death from any cause. Regimen-related toxicity was assessed using the Bearman toxicity score.[20]
Statistical analysis
Demographic and clinical characteristics were described and compared using the chi-square and Fisher’s exact tests for dichotomous variables. Survival probabilities were estimated by means of the Kaplan-Meier method. The multivariate Cox proportional model and survival analysis were calculated with SPSS software (SPSS 22.0, Chicago, IL, USA). Competing risk analyses were used to calculate the cumulative incidence of engraftment, GVHD, relapse, and TRM using the Gray test.[21] Hazard ratios (HRs) for OS were estimated from univariate and multivariate Cox regression analyses. All of the factors with P < 0.1 in the univariate analysis were included in a multivariate regression, and P < 0.05 was considered to be statistically significant. All of the reported P values were based on two-sided hypothesis tests. Data analyses were primarily conducted with SPSS software (SPSS Inc., Chicago, IL), and R software (version 2.6.1; http://www.r-project.org) was used for competing risks analysis. The sample size was calculated according to the assumption that the 2-year TRM for patients with an HCT-CI score of ≥ 3 was approximately 34% on the basis of published data.[3,4] The null hypothesis was a 2-year TRM of 34%, and the alternative hypothesis was a 2-year TRM of 25% with the Bu/Cy/Flu/ATG regimen. The noninferiority margin was set to 0.09. Enrollment of 72 patients would provide 90.08% power to test the null hypothesis with a one-sided significance of 2.5%.
Results
Patient characteristics
A total of 72 patients were enrolled in our study, including 40 males and 32 females. The median age was 52 (18-66) years old. The underlying disease included 33 patients of AML, 20 patients of MDS, 16 patients of acute lymphoblastic leukemia (ALL), and 3 patients of CMML. The most common comorbidities among these patients were prior solid malignancy (36.1%) and infection which could be controlled before transplantation (29.2%), followed by moderate pulmonary disease (25.0%), severe pulmonary disease (23.6%), and diabetes (20.8%). The HCT-CI scores of the patients were 3, 4, 5, 6 and 7, with 45 (62.5%), 20 (27.8%), 5 (6.9%), 1 (1.4%) and 1 (1.4%) patients, respectively. The median follow-up time of the survivors was 439 days (ranging from 98 to 1435 days). The baseline clinical characteristics of the patients are shown in Table 1. A detailed list of basic information regarding the age, sex, and HCT-CI scores of all enrolled patients is shown in Supplementary Table 1.
The baseline clinical characteristics of the patients with HCT-CI ≥ 3
| Characteristics | Parameters |
|---|---|
| Patient age at HSCT, median (range), yr | 52 (18-66) |
| Patient sex, male/female, n (%) | 42 (58.3)/30 (41.7) |
| Disease, n (%) | |
| AML | 33 (45.8) |
| ALL | 16 (22.2) |
| MDS | 20 (27.8) |
| CMML | 3 (4.2) |
| Disease | |
| AML | |
| CR1/CR2/ ≥ CR3/NR or relapse | 28/2/0/3 |
| ALL | |
| CR1/CR2/ ≥ CR3/NR or relapse | 11/5/0/0 |
| MDS | |
| Low/int-1/int-2/high | 0/6/13/1 |
| CMML | |
| Low/int-1/int-2/high | 1/0/1/1 |
| Disease risk index (low/Intermediate/high) | 9/45/18 |
| HCT-CI, n (%) | |
| 3 | 45 (62.5) |
| 4 | 20 (27.8) |
| ≥5 | 7 (9.7) |
| Comorbidity, n (%) | |
| Obesity | 0 |
| Pulmonary-morderate | 18 (25.0) |
| Pulmonary-severe | 17 (23.6) |
| Infection | 21 (29.2) |
| Arrhythmia | 3 (4.2) |
| Diabetes | 15 (20.8) |
| Cerebrovascular | 8 (11.1) |
| Hepatic-mild | 6 (8.3) |
| Hepatic-moderate/severe | 5 (6.9) |
| Rheumatologic | 1 (1.4) |
| Peptic ulcer | 0 |
| Renal | 1 (1.4) |
| Prior solid malignancy | 26 (36.1) |
| Cardiovascular | 4 (5.6) |
| Heart valve disease | 2 (2.8) |
| Inflamatory bowel disease | 0 |
| Depression/anxiety | 1 (1.4) |
| Donor-recipient ABO blood type, n (%) | |
| Match | 37 (51.4) |
| Mismatch | 35 (48.6) |
| Donor sex, male/female, n (%) | 45 (62.5)/27 (37.5) |
| Source of stem cell, n (%) | |
| Bone marrow and peripheral blood | 22 (30.6) |
| Peripheral blood | 50 (69.4) |
| Letermovir in CMV prophylaxis | |
| Yes | 9 (12.5) |
| No | 63 (87.5) |
| DLI or maintenance therapy post-transplant | |
| DLI | 3 (4.1) |
| Interferon | 2 (2.8) |
| No intervention | 67 (93.1) |
| MNC, 108/kg, median (range) | 8.79 (5.56-20.18) |
| CD34, 106/kg, median (range) | 3.21 (0.83-14.10) |
HSCT: hematopoietic stem cell transplantation; ALL: acute lymphoblastic leukemia; AML: Acute myeloid leukemia; MDS: myelodysplastic syndrome; CMML: chronic myelomonocytic leukemia; HCT-CI: hematopoietic cell transplantation comorbidity index; MNC: mononuclear cells; CMV: cytomegalovirus; DLI: donor lymphocyte infusion.
Engraftment, GVHD and infection
All of the patients achieved neutrophil engraftment. The median time of neutrophil engraftment was 13 (10-33) days. However, 3 (4.2%) patients did not achieve platelet engraftment due to a TRM, and another one (1.4%) patients did not achieve platelet engraftment till the last follow-up. The median time of platelet engraftment was 15 (9-163) days.
A total of 26 patients (36.1%) had acute GVHD. The median onset time of aGVHD was 29 (13-269) days after transplantation. The cumulative incidence of grade II-IV aGVHD and grade III-IV aGVHD at day 100 post-HSCT was 20.8% (Figure 1A) and 5.6% (Figure 1B), respectively.
GVHD and virus infection. (A) The cumulative incidence of grade II-IV aGVHD at day 100 post-HSCT. (B) The cumulative incidence of grade III-IV aGVHD at day 100 post-HSCT. (C) The cumulative incidence of CMV viremia at day 100 post-HSCT. (D) The cumulative incidence of EBV reactivation at day 100 post-HSCT. aGVHD: acute graft-versus-host disease; GVHD: graft-versus-host disease; HSCT: hematopoietic stem cell transplantation; CMV: cytomegalovirus; EBV: Epstein-Barr virus.
CMV viremia was observed in 54 (75.0%) cases, with a median onset time of 37 (21-146) days post-HSCT. The cumulative incidence of CMV viremia at day 100 post-HSCT was 72.2%, as shown in Figure 1C. Additionally, 24 (33.3%) cases experienced EBV reactivation, with a median onset time of 50 (34-172) days post-HSCT. The cumulative incidence of EBV reactivation at day 100 post-HSCT was 31.9%, as shown in Figure 1D. Among the 24 patients who experienced EBV reactivation, 10 (13.9%) patients presented with EBV post-transplant lymphoproliferative disease (PTLD).
Regimen-related toxicity (RRT)
Within 30 days post transplantation, 86.1% of the patients exhibited varying degrees of RRT). Of these patients, 50% experienced gastrointestinal toxicity, with 33 cases of grade I and 3 cases of grade II. Additionally, 62.5% of patients experienced hepatic toxicity, with 24 cases of grade I and 21 cases of grade II. Cardiac toxicity was observed in 13.9% of patients, with 1 case of grade I, 8 cases of grade II and 1 case of grade III. Some patients experienced grade I renal (16.7%) and stomatitis-related (18.1%) toxicity, while 2.8% of patients developed grade II bladder toxicity. For more detailed information, please refer to Table 2.
RRTs within 30 days post-HSCT
| Index | n (%) |
|---|---|
| Numbers of organs involved | |
| None | 10 (13.9) |
| One organ | 26 (36.1) |
| Two organs | 22 (30.5) |
| Three organs | 9 (12.5) |
| Four organs | 3 (4.2) |
| Five organs | 2 (2.8) |
| Frequency of involvement in each organ | |
| Gastrointestinal toxicity | 36 (50.0) |
| Grade I | 33 (45.8) |
| Grade II | 3 (4.2) |
| Hepatic toxicity | 45 (62.5) |
| Grade I | 24 (33.3) |
| Grade II | 21 (29.2) |
| Cardiac toxicity | 10 (13.9) |
| Grade I | 1 (1.4) |
| Grade II | 8 (11.1) |
| Grade III | 1 (1.4) |
| Renal toxicity | 12 (16.7) |
| Grade I | 12 (16.7) |
| Stomatitis toxicity | 13 (18.1) |
| Grade I | 13 (18.1) |
| Bladder toxicity | 2 (2.8) |
| Grade II | 2 (2.8) |
HSCT: hematopoietic stem cell transplantation; RRTs: regimen-related toxicities.
Clinical outcomes
The last follow-up was on April 9, 2023. Sixteen of the patients died during this study. The primary cause of death was infection, which accounted for 9 cases, followed by transplant-related thrombotic microangiopathy with 4 cases. There was also 1 case each of relapse, cerebral hemorrhage, and myocardial infarction. The cumulative incidence of 30-day, 100-day, 1-year and 2-year TRM was 0%, 4.2%, 21.4% and 25.1%, respectively (Figure 2A). The cumulative incidence of 2-year relapse was 8.6%, as depicted in Figure 2B. The probabilities of 2-year OS and LFS were 71.9% and 65.6%, respectively, as shown in Figure 2C-D. The main clinical outcome was then analyzed according to disease type. The 2-year TRM of acute leukemia and non-acute leukemia (MDS or CMML) were 21.6% and 34.7% (P = 0.093), and the 2-year cumulative incidence of relapse (CIR) were 10.3% and 4.5% (P = 0.438), respectively. The 2-year OS was 75.2% and 64.3%, respectively (P = 0.133). The 2-year LFS was 67.1% and 60.5%, respectively (P = 0.251; Figure 3A-D).
Outcomes. (A) The cumulative incidence of 2-year TRM. (B) The cumulative incidence of 2-year relapse. (C) The probabilities of 2-year overall survival. (D) The probabilities of 2-year LFS. LFS: leukemia-free survival; OS: overall survival; HSCT: hematopoietic stem cell transplantation; TRM: treatment-related mortality.
Outcomes of disease subtype. (A) The cumulative incidence of 2-year TRM. (B) The cumulative incidence of 2-year relapse. (C) The probabilities of 2-year overall survival. (D) The probabilities of 2-year LFS. TRM: treatment-related mortality; HSCT: hematopoietic stem cell transplantation; LFS: leukemia-free survival; MDS: myelodysplastic syndrome; CMML: chronic myelomonocytic leukemia.
Univariate analysis, including age, sex, HCT-CI score, underlying diseases (acute leukemia or nonacute leukemia), disease risk index, donor sex, ABO blood type, source of stem cells (bone marrow plus peripheral blood vs. peripheral blood), and grafts (mononuclear cell count and CD34+ cell count), was performed for all patients. The results of the univariate analysis showed that no factors were associated with TRM, LFS, OS, or CIR.
Discussion
For the first time in a prospective study, we have shown that the modified Bu/Cy/Flu/ATG reduced-toxicity conditioning regimen followed by haplo-HSCT is a viable option for patients with high HCI-CI scores. This novel protocol resulted in acceptable TRM rates, along with successful engraftment, GVHD, relapse and survival outcomes. These findings show that haplo-HSCT holds great promise as a potential treatment option for patients with HCT-CI score ≥ 3. Previous studies concerning haplo-HSCT following reduced intensity conditioning have indicated OS rates ranging from 44% to 56%, disease-free survival (DFS) rates between 34% and 44%, incidence of relapse rates from 45% to 57.8%, and non-relapse mortality (NRM) rates ranging from 5.0% to 23%.[22, 23, 24, 25] Pan et al. investigated the safety and efficacy of the reduced-intensive conditioning (RIC) regimen (Bu2Flu or Bu3Flu) ATG-based haplo-HSCT in older or unfit patients. The 2-year OS and 2-year DFS in whole cohort were 67.7% and 61.4% respectively. The 2-year cumulative incidence rates of relapse and NRM rates in whole cohort were 27.5% and 11.6% respectively.[26] The aforementioned studies reported suboptimal survival outcomes in comparison to our research findings.
It is widely recognized that a high HCT-CI score is indicative of a greater risk of complications with organ function. In this study, we observed that no patients died within the first 30 days post-transplantation, and there was an absence of regimen-related toxic death events. In this cohort, although 83% of patients experienced early toxicity related to transplantation within 30 days, grade I RRT made up 70.3% of cases, and grade III RRT was only reported in one case. In addition, the cumulative incidence of 30-day and 100-day TRM was relatively low, demonstrating that the early toxicity of the modified Bu/Cy/Flu/ATG regimen was manageable. However, it was remarkable that the TRM between day 100 and 1 year increased substantially, infection was the main cause of increased TRM.
Chang et al. reported that unmanipulated haplo-HSCT patients with HCT-CI scores of ≥ 3 who received Bu/Cy/ ATG conditioning regimen exhibited a high probability of NRM (33.1%).[4] Mo et al. confirmed that the 2-year cumulative incidence of NRM in patients with HCT-CI scores of ≥ 3 who received haplo-HSCT of Bu/Cy/ ATG regimen was 34.3%.[3] In this study, we observed that this reduced-toxicity conditioning could reduce the 2-year cumulative incidence of NRM to 25.6%, indicating that this novel protocol was promising for patients with HCT-CI scores ≥ 3.
The use of Flu might play an important role. Liu et al. performed an open-label, randomized phase III trial to compare the outcomes of the Bu/Flu regimen with those of the Bu/Cy regimen for AML in haplo-HSCT. Grade 3 RRT was reported for 0 of 191 patients following the Bu/ Flu regimen and 9 (4.7%) of 190 patients following the Bu/ Cy regimen (P = 0.002), while the 1-year TRM was 7.2% and 14.1% (P = 0.041), respectively, indicating that the Bu/ Flu regimen has a lower TRM and RRT for patients with AML undergoing haplo-HSCT compared with the Bu/ Cy regimen.[27] In another study from the same team, the incidences of total and III-IV RRT were 94.4% and 81.5% (P = 0.038) and 16.7% and 0.0% (P = 0.002), respectively, in the Bu/Cy and Bu/Flu groups. The 5-year TRM rates were 18.8 ± 6.9% and 9.9 ± 6.3% (P = 0.104), suggesting that the use of Bu/Flu was associated with reduced RRT without a significant impact on NRM for AML patients in CR1 undergoing allo-HSCT.[28] Wang JM et al. reported that the incidences of diarrhea and severe oral mucositis within the first 30 days post-transplantation were lower in the Bu/Flu/cytarabine group [28.57% vs. 65.45%, P < 0.001; 51.79% vs. 70.91%, P = 0.039)] than in the Bu/Cy group, and both regimens achieved a similar TRM rate.[29]
We have attempted the complete replacement of Cy by Flu; however, primary engraftment failure with this modified regimen seemed to be higher than that with the Bu/ Cy/ATG regimen in elderly patients or in patients with severe comorbidities who underwent haplo-HSCT. Sun et al. reported that the cumulative incidence of primary engraftment failure was higher in the Bu-Flu group than in the Bu-Cy group (17.6% vs. 3.0%, P = 0.04).[30] This suggests that fludarabine may not be sufficient to replace Cy. Under this condition, a novel regimen with a combination of reduced doses of Cy and fludarabine has been introduced. Our previous study demonstrated that this modified Bu/ Cy/Flu/ATG regimen did not affect engraftment and may be an option for older patients who undergo haplo-HSCT.[10] However, the above literature focused on patients over 55 years old who underwent the Bu/Flu/Cy/ATG conditioning regimen during haploidentical transplantation. In our current study, we found that all of the patients achieved neutrophil engraftment, suggesting that this novel regimen consisting of low doses of Cy and fludarabine has an excellent engraftment profile.
Prevention and treatment of relapse is an important issue in HSCT.[31] Another concern is that reduced organ damage by the Bu/Flu regimen might cause a lower anti-leukemic effect or a higher relapse rate than the Bu/Cy regimen. In the present study, it was noted that the relapse rate of this novel regimen did not seem to increase compared to our historical cohort,[3] suggesting that this novel conditioning regimen not only reduced toxicity but also had a graft-versus-leukemia (GVL) effect. In the present study, we also confirmed that the incidence of aGVHD was comparable in older patients with the same modified Bu/Cy/Flu/ATG conditioning regimen[10] or even lower in patients whose HCT-CI scores ≥ 3 with standard Bu/Cy/ ATG conditioning regimen.[3] The cumulative incidence of CMV viremia at day 100 post-HSCT was 72.2%, but this result was in a pre-detemovir prophylaxis era. In today’s era of widespread use of letmovir, the incidence of CMV viremia may decrease. We found that the incidence of EBV reactivation and PTLD was high by using this modified Bu/ Cy/Flu/ATG regimen. Anderlini et al. observed that EBV reactivation and viremia in 35% of severe aplastic anemia patients underwent allo-HSCT with Flu, Cy and ATG from a matched related or URD.[32] Gao et al. demonstrated that a fludarabine-containing conditioning regimen was one of the risk factors for PTLD after haplo-HSCT.[33] So further exploration of the mechanism and how to prevent EBV infection may be a way to take this conditioning regimen further.
It is important to note that this study has several limitations. Firstly, it was found that the main comorbidities of patients with high HCT-CI scores were pulmonary disease, infection, and a prior solid tumor in this study. Additional studies are necessary to confirm the comorbidities of crucial organs, such as cardiac disease and renal dysfunction. Secondly, since the sample size was relatively small, the results need to be interpreted with caution. Additionally, since this was a single-arm clinical trial, a comparison with the standard myeloablative conditioning cohort could not be made. Thus, the baseline characteristics of cases may be biased when comparisons are made with historical control cohorts. In the future, multicenter, randomized controlled trials should be conducted to further verify the safety and efficacy of this novel regimen.
Overall, this novel conditioning regimen is a viable choice for patients whose HCT-CI scores ≥ 3. It has a low risk of TRM and leads to successful engraftment with favorable outcomes in terms of GVHD, relapse, and OS. However, multicenter randomized controlled head to head comparative trials should be conducted in the future to validate the results.
Funding statement: This work was supported by the National Key Research and Development Program of China (No. 2022YFA1103300), Major Program of the National Natural Science Foundation of China (No. 82293630), and Key Program of the National Natural Science Foundation of China (No. 81930004).
Acknowledgements
None.
-
Author Contributions
Wei Sun Writing—Original draft, Yu-Qian Sun Writing—Review and Editing, Xiao-Dong Mo Data curation, Rui Ma Data curation, Yun He Data curation, Yuan-Yuan Zhang Data curation, Yu-Hong Chen Data curation, Feng-Rong Wang Data curation, Huan Chen Data curation, Yao Chen Data curation, Chen-Hua Yan Data curation, Wei Han Data curation, Lan-Ping Xu Data curation, Yu Wang Data curation, Xiao-Hui Zhang Data curation, Kai-Yan Liu Data curation, Xiao-Jun Huang Writing—Review and Editing, Supervision, Project administration, and Funding acquisition.
-
Ethical Approval
This study was approved by the Ethics Committee of Peking University People’s Hospital. Patient Consent Statement (ClinicalTrials. gov: NCT03412409).
-
Informed Consent
Not applicable.
-
Conflict of Interest
The authors declared no potential conflicts of interest.
-
Use of Large Language Models, AI and Machine Learning Tools
None declared.
-
Data Availability Statement
All data is included in the manuscript.
References
1 Chang YJ, Wang Y, Xu LP, Zhang X, Chen H, Chen YH, et al. Haploidentical donor is preferred over matched sibling donor for pre-transplantation MRD positive ALL: a phase 3 genetically randomized study. J Hematol Oncol 2020;13:27.10.1186/s13045-020-00860-ySearch in Google Scholar PubMed PubMed Central
2 Wang Y, Liu QF, Xu LP, Liu KY, Zhang XH, Ma X, et al. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood 2015;125:3956–3962.10.1182/blood-2015-02-627786Search in Google Scholar PubMed
3 Mo XD, Xu LP, Liu DH, Zhang XH, Chen H, Chen YH, et al. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) is an outcome predictor for partially matched related donor transplantation. Am J Hematol 2013;88:497–502.10.1002/ajh.23443Search in Google Scholar PubMed
4 Chang YJ, Wang HT, Xu LP, Wang Y, Liu KY, Zhang XH, et al Combined model of the EBMT score modified model and the HCT-CI improves the stratification of high-risk patients undergoing unmanipulated haploidentical blood and marrow transplantation. Leuk Lymphoma 2016;57:2133–2139.10.3109/10428194.2015.1124990Search in Google Scholar PubMed
5 McDonald GB, Slattery JT, Bouvier ME, Ren S, Batchelder AL, Kalhorn TF, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003;101:2043–2048.10.1182/blood-2002-06-1860Search in Google Scholar PubMed
6 Bornhäuser M, Storer B, Slattery JT, Appelbaum FR, Deeg HJ, Hansen J, et al. Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells. Blood 2003;102:820–826.10.1182/blood-2002-11-3567Search in Google Scholar PubMed
7 de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood 2004;104:857–864.10.1182/blood-2004-02-0414Search in Google Scholar PubMed
8 Wang FR, Huang XJ, Liu DH, Chen H, Wang Y, Tang FF, et al. [The efficacy and safety of modified busulfan/fludarabine conditioning regimen in elderly or drug-intolerable patients with hematologic malignancies]. Zhonghua Nei Ke Za Zhi 2013;52:1028–1032.Search in Google Scholar
9 Lee SE, Kim HJ, Min WS, Cho BS, Eom KS, Kim YJ, et al. Favorable outcomes of intravenous busulfan, fludarabine, and 400cGy total body irradiation-based reduced-intensity conditioning allogeneic stem cell transplantation for acute myelogenous leukemia with old age and/or co-morbidities. Int J Hematol 2010;92:342–350.10.1007/s12185-010-0649-ySearch in Google Scholar PubMed
10 Sun YQ, Han TT, Wang Y, Yan CH, Wang FR, Wang ZD, et al. Haploidentical stem cell transplantation with a novel conditioning regimen in older patients: a prospective single-arm phase 2 study. Front Oncol 2021;11:639502.10.3389/fonc.2021.639502Search in Google Scholar PubMed PubMed Central
11 Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912–2919.10.1182/blood-2005-05-2004Search in Google Scholar PubMed PubMed Central
12 Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant 2009;15:257–265.10.1016/j.bbmt.2008.11.025Search in Google Scholar
13 Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplantation 2006;38:291–297.10.1038/sj.bmt.1705445Search in Google Scholar
14 Wang Y, Chen H, Chen J, Han M, Hu J, Hu J, et al. The consensus on the monitoring, treatment, and prevention of leukemia relapse after allogeneic hematopoietic stem cell transplantation in China. Cancer Lett 2018;438:63–75.10.1016/j.canlet.2018.08.030Search in Google Scholar
15 Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM, et al. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophos-phamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biol Blood Marrow Transplant 2012;18:1007–1011.10.1016/j.bbmt.2012.04.014Search in Google Scholar
16 Han TT, Xu LP, Liu DH, Liu KY, Fu HX, Zhao XY, et al. Cytomegalovirus is a potential risk factor for late-onset hemorrhagic cystitis following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2014;89:55–61.10.1002/ajh.23584Search in Google Scholar
17 Pei XY, Zhao XY, Chang YJ, Liu J, Xu LP, Wang Y, et al. Cytomegalovirusspecific T-cell transfer for refractory cytomegalovirus infection after haploidentical stem cell transplantation: the quantitative and qualitative immune recovery for cytomegalovirus. J Infect Dis 2017;216:945–956.10.1093/infdis/jix357Search in Google Scholar
18 Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995;15:825–828.Search in Google Scholar
19 Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11:945–956.10.1016/j.bbmt.2005.09.004Search in Google Scholar
20 Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988;6:1562–1568.10.1200/JCO.1988.6.10.1562Search in Google Scholar
21 Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999;18:695–706.10.1002/(SICI)1097-0258(19990330)18:6<695::AID-SIM60>3.3.CO;2-FSearch in Google Scholar
22 Sugita J, Kagaya Y, Miyamoto T, Shibasaki Y, Nagafuji K, Ota S, et al. Myeloablative and reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide. Bone Marrow Transplantation 2019;54:432–441.10.1038/s41409-018-0279-1Search in Google Scholar
23 Sugita J, Kawashima N, Fujisaki T, Kakihana K, Ota S, Matsuo K, et al. HLA-haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide after busulfan-containing reduced-intensity conditioning. Biol Blood Marrow Transplant 2015;21:1646–1652.10.1016/j.bbmt.2015.06.008Search in Google Scholar PubMed
24 Solh MM, Hinojosa G, Laporte J, Solomon SR, Morris LE, Zhang X, et al. A phase II trial of melphalan based reduced-intensity conditioning for transplantation of T-replete HLA-haploidentical peripheral blood stem cells with posttransplant cyclophosphamide in patients with hematologic malignancies. Adv Hematol 2021;2021:8868142.10.1155/2021/8868142Search in Google Scholar PubMed PubMed Central
25 Higuchi K, Sawada A, Kondo O, Okada Y, Tsujimoto H, Ioi A, et al. HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning with very low-dose antithymocyte globulin for relapsed/refractory acute leukemia in pediatric patients: a single-institution retrospective analysis. Int J Hematol 2022115:406–413.10.1007/s12185-021-03270-zSearch in Google Scholar PubMed
26 Pan M, Wu Y, Yang L, Zhu P, Shi J, Lai X, et al. Reduced intensity conditioning regimen of fludarabine, busulfan, ATG based haploidentical stem cell transplantation for older or unfit patients. Ann Hematol 2024;103:3105–3119.10.1007/s00277-024-05819-4Search in Google Scholar PubMed
27 Ling Y, Xuan L, Xu N, Huang F, Fan Z, Guo Z, et al. Busulfan plus fludarabine compared with busulfan plus cyclophosphamide for AML undergoing HLA-haploidentical hematopoietic cell transplantation: a multicenter randomized phase III trial. J Clin Oncol 2023;41:4632–4642.10.1200/JCO.23.00101Search in Google Scholar PubMed
28 Liu H, Zhai X, Song Z, Sun J, Xiao Y. Nie D, et al. Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study. J Hematol Oncol 2013;6:15.10.1186/1756-8722-6-15Search in Google Scholar PubMed PubMed Central
29 Zhang WP, Wang ZW, Hu XX, Chen J, Yang D, Song XM, et al. Preconditioning with fludarabine, busulfan and cytarabine versus standard BuCy2 for patients with acute myeloid leukemia: a prospective, randomized phase II study. Bone Marrow Transplant 2019;54:894–902.10.1038/s41409-018-0356-5Search in Google Scholar PubMed
30 Sun YQ, Xu LP, Zhang XH, Liu DH, Chen H, Wang Y, et al. A retrospective comparison of BU-fludarabine and BU–CY regimens in elderly patients or in patients with comorbidities who received unmanipulated haploidentical hematopoietic SCT. Bone Marrow Transplant 2015;50:601–603.10.1038/bmt.2014.303Search in Google Scholar PubMed
31 Wang Y, Chang YJ, Chen J, Han M, Hu J, Hu J, et al. Consensus on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation in China: 2024 update. Cancer Lett 2024;605:217264.10.1016/j.canlet.2024.217264Search in Google Scholar PubMed
32 Anderlini P, Acholonu SA, Okoroji GJ, Bassett RE, Shpall EJ, Qazilbas, MH, et al. Fludarabine, cyclophosphamide, and antithymocyte globulin for matched related and unrelated allogeneic stem cell transplant in severe aplastic anemia. Leuk Lymphoma 2011;52:137–141.10.3109/10428194.2010.524328Search in Google Scholar PubMed PubMed Central
33 Gao XN, Lin J, Wang LJ, Li F, Li HH, Wang SH, et al. Risk factors and clinical outcomes of Epstein–Barr virus DNAemia and post-transplant lymphoproliferative disorders after haploidentical and matched-sibling PBSCT in patients with hematologic malignancies. Ann Hematol 2019;98:2163–2177.10.1007/s00277-019-03742-7Search in Google Scholar PubMed
© 2025 Wei Sun, Yuqian Sun, Xiaodong Mo, Rui Ma, Yun He, Yuanyuan Zhang, Yuhong Chen, Fengrong Wang, Huan Chen, Yao Chen, Chenhua Yan, Wei Han, Lanping Xu, Yu Wang, Xiaohui Zhang, Kaiyan Liu, Xiaojun Huang, published by De Gruyter on behalf of the SMP
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Articles in the same Issue
- Perspective
- Crosstalk between cardiac dysfunction and outcome of liver cirrhosis: Perspectives from evidence-based medicine and holistic integrative medicine
- Telemedicine strategies in older patients with cardiovascular diseases
- Clinical significance of portal vein thrombosis in patients with decompensated cirrhosis: A still matter of debate
- Review Article
- Eupatilin unveiled: An in-depth exploration of research advancements and clinical therapeutic prospects
- Original Article
- Benzo[b]fluoranthene is involved in idiopathic membranous nephropathy by inducing podocyte injury
- A novel and safe protocol for patients with severe comorbidity who undergo haploidentical hematopoietic stem cell transplantation: A single-center prospective study
- Deciphering the role of ELAVL1: Insights from pan-cancer multiomics analyses with emphasis on nasopharyngeal carcinoma
- Nano particle loaded EZH2 inhibitors: Increased efficiency and reduced toxicity for malignant solid tumors
- An automated human–machine interaction system enhances standardization, accuracy and efficiency in cardiovascular autonomic evaluation: A multicenter, open-label, paired design study
- Rapid Communication
- Comparison of predicting value of triglyceride‑glucose indices family in cardiovascular disease risk over time: Insights from a 9-year nationwide prospective cohort study
Articles in the same Issue
- Perspective
- Crosstalk between cardiac dysfunction and outcome of liver cirrhosis: Perspectives from evidence-based medicine and holistic integrative medicine
- Telemedicine strategies in older patients with cardiovascular diseases
- Clinical significance of portal vein thrombosis in patients with decompensated cirrhosis: A still matter of debate
- Review Article
- Eupatilin unveiled: An in-depth exploration of research advancements and clinical therapeutic prospects
- Original Article
- Benzo[b]fluoranthene is involved in idiopathic membranous nephropathy by inducing podocyte injury
- A novel and safe protocol for patients with severe comorbidity who undergo haploidentical hematopoietic stem cell transplantation: A single-center prospective study
- Deciphering the role of ELAVL1: Insights from pan-cancer multiomics analyses with emphasis on nasopharyngeal carcinoma
- Nano particle loaded EZH2 inhibitors: Increased efficiency and reduced toxicity for malignant solid tumors
- An automated human–machine interaction system enhances standardization, accuracy and efficiency in cardiovascular autonomic evaluation: A multicenter, open-label, paired design study
- Rapid Communication
- Comparison of predicting value of triglyceride‑glucose indices family in cardiovascular disease risk over time: Insights from a 9-year nationwide prospective cohort study
