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1.
Addition of venetoclax to myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in high-risk AML
Cao, X. Y., Chen, J. Q., Wang, H., Ma, W., Liu, W. W., Zhang, F. F., Xue, S., Dong, L., Liu, T., Zhao, X. Z., et al
Annals of medicine. 2023;55(1):388-400
Abstract
BACKGROUND Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated. OBJECTIVE To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML. STUDY DESIGN From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed. RESULTS At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52-632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2-36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9-26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5-81.4%) and 3.2% (95%CI, 0.4-22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5-93.6%) and 81.3% (95%CI, 64.2-93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8-26.3%) and 11.7% (95%CI, 3.9-35.0%). CONCLUSION Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.
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2.
Myeloablative dose of busulfan and fludarabine combined with in vivo T-cell depletion is a safe and effective conditioning for acute myeloid leukaemia and myelodysplastic syndrome patients
Avenoso, D., Mehra, V., Slonim, L. B., de Farias, M., Alshehri, H., Bouziana, S., Krishnamurthy, P., Kulasekararaj, A., Dazzi, F., Wood, H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Allogeneic haematopoietic stem cell transplant (HSCT) is a curative strategy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplant related mortality (TRM) using the HCT-CI score and an arbitrary upper limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. Reduced toxicity conditioning regimens are additional methods to deliver safe and effective myeloablation. OBJECTIVES Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients aged ≥55 years. Secondary objectives were total OS, TRM, graft versus-host disease (GVHD) and GVHD-relapse-free survival (GRFS). RESULTS The two years' OS in patients aged < 55 and aged ≥ 55 were 72% and 51%, respectively. In patients aged ≥55 with an HCT-CI <2, the estimated two years' OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the two-year OS was 43%, with median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. CONCLUSIONS FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients aged ≥55 in absence of comorbidities, and that age should not be the sole determinate of conditioning intensity.
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3.
Appropriate pre-transplant strategy for patients with myelodysplastic syndromes receiving allogeneic haematopoietic stem cell transplantation after myeloablative conditioning
Wang, H., Wang, Q., Qi, J., Li, X., Chu, T., Qiu, H., Fu, C., Tang, X., Ruan, C., Wu, D., et al
Frontiers in immunology. 2023;14:1146619
Abstract
PURPOSE Appropriate pre-transplant strategies in patients with myelodysplastic syndromes (MDS) remain challenging. We sought to assess the effect of different pre-transplant therapies and transplantation interval times on patient prognosis. METHODS We retrospectively analysed clinical data for 371 consecutive MDS patients after myeloablative transplantation between 2007 and 2019. RESULTS The median age of the patients was 38 years (range, 12-64 years). A total of 114 patients (31%) received supportive care (SC), 108 (29%) hypomethylating agents (HMAs), and 149 (40%) chemotherapy-based therapy before transplantation. In patients who received HMA or SC, there was no significant difference in overall survival (OS; P=0.151) or relapse-free survival (RFS; P=0.330), except that HMA-treated patients had a lower rate of non-relapse mortality (5-year NRM: 18% vs. 32%, P=0.035). However, compared with patients who received HMA, those who received chemotherapy-based therapy had a lower 5-year OS rate (56% vs. 69%, P=0.020) and a slightly higher 5-year NRM rate (28% vs. 18%, P=0.067). Compared to the delayed transplant group (transplant interval ≥6 months), the early transplant group (transplant interval <6 months) had a superior 5-year OS (66% vs. 51%, P=0.001) and a lower 5-year cumulative incidence of NRM (22% vs. 36%, P=0.001). CONCLUSION The findings of the study indicate that receiving an appropriate pre-transplant strategy (SC/HMA + <6 months) significantly improves OS and decreases NRM in MDS patients after myeloablative transplantation.
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4.
Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis
Luo, C., Wu, G., Huang, X., Ding, Y., Huang, Y., Song, Q., Hou, Y., Chen, J., Li, X., Xu, S.
Bone Marrow Transplantation. 2023;58(2):175-185
Abstract
The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation.
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5.
Improved myeloablative conditioning regimen for allogeneic stem cell transplantation in adult patients with chronic myelomonocytic leukaemia
Zhang, T., Liu, X., Fei, H., Zhang, L., Ma, R., Shen, Y., Pang, A., Yang, D., Chen, X., Zhang, R., et al
British journal of haematology. 2023;200(2):256-260
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6.
Association Between the Magnitude of Intravenous Busulfan Exposure and Development of Hepatic Veno-Occlusive Disease in Children and Young Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation
Bognàr, T., Bartelink, I. H., Egberts, T. C. G., Rademaker, C. M. A., Versluys, A. B., Slatter, M. A., Kletzel, M., Nath, C. E., Cuvelier, G. D. E., Savic, R. M., et al
Transplantation and cellular therapy. 2022;28(4):196-202
Abstract
Intravenous busulfan is widely used as part of myeloablative conditioning regimens in children and young adults undergoing allogeneic hematopoietic cell transplantation (HCT). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious clinical problem observed with busulfan-based conditioning HCT. The development of VOD/SOS may be associated with busulfan exposure. Getting more insight into the association between busulfan exposure and the development of VOD/SOS enables further optimization of dosing and treatment strategies. The objective of this study was to assess the association between the magnitude of busulfan exposure and the occurrence of VOD/SOS in children and young adults undergoing myeloablative conditioning with a busulfan-containing regimen before allogeneic HCT. In this observational study we included all patients who underwent allogeneic HCT with intravenous busulfan as part of the conditioning regimen at 15 pediatric transplantation centers between 2000 and 2015. The endpoint was the development of VOD/SOS. The magnitude of busulfan exposure was estimated using nonlinear mixed effect modeling and expressed as the maximal concentration (Cmax; day 1 and day 1 to 4 Cmax), cumulative area under the curve (AUC; day 1, highest 1-day AUC in 4 days, and 4-day cumulative AUC), cumulative time above a concentration of 300 µg/L, and clearance on day 1. A total of 88 out of 697 patients (12.6%) developed VOD/SOS. The number of alkylators in the conditioning regimen was a strong effect modifier; therefore we stratified the regression analysis for the number of alkylators. For patients receiving only busulfan as one alkylator (36.3%, n = 253), cumulative busulfan exposure (>78 mg × h/L) was associated with increased VOD/SOS risk (12.6% versus 4.7%; odds ratio [OR] = 2.95, 95% confidence interval [CI] 1.13 to 7.66). For individuals receiving busulfan with one or two additional alkylators (63.7%, n = 444), cumulative busulfan exposure (≤78 and >78 mg × h/L) did not further increase the risk of VOD/SOS (15.4% versus 15.2%; OR = 1.03, 95% CI 0.61 to 1.75). The effect of the magnitude of busulfan exposure on VOD/SOS risk in children and young adults undergoing HCT is dependent on the number of alkylators. In patients receiving busulfan as the only alkylator, higher cumulative busulfan exposure increased the risk of VOD/SOS, whereas in those receiving multiple alkylators, the magnitude of busulfan exposure did not further increase this risk.
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7.
Clofarabine and busulfan myeloablative conditioning in allogeneic hematopoietic cell transplant for patients with active myeloid malignancies
Connor, M. P., Loren, A. W., Hexner, E. O., Martin, M. E., Gill, S. I., Luger, S. M., Mangan, J. K., Perl, A. E., McCurdy, S. R., Pratz, K. W., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplant (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and non-relapse mortality. A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been described to exhibit anti-leukemic activity with acceptable toxicity in patients ≤ 70 years old. OBJECTIVES To describe clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. STUDY DESIGN In a single-center, retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free (EFS) and overall survival (OS), cumulative incidence of relapse, non-relapse mortality (NRM), and incidence and severity of acute and chronic graft-versus-host disease (GVHD). RESULTS We identified 69 patients with a median age of 60 years (range 22-70). Most patients had relapsed/refractory or primary refractory acute myeloid leukemia (AML, n = 55), or refractory myelodysplastic syndrome (MDS, n = 12); one patient had chronic myeloid leukemia and one had blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 after transplant. Two-year EFS and OS were 30% (95% CI 20-44) and 40% (95% CI 29-54), respectively. Patients with AML had 2-year EFS and OS of 28% (95% CI 18-44) and 38% (95% CI 27-54), respectively; those with MDS had 2-year EFS and OS of 47% (95% CI 25-88) and 56% (95% CI 33-94), respectively. Cumulative incidence of relapse at 2 years was 39% (95% CI 27-51) for all patients: 45% (95% CI 31-58) in AML and 18% (95% CI 2-45) in MDS. NRM at 2 years was 31% (95% CI 20-42): 27% (95% CI 15-39) in AML and 35% (95% CI 10-63) in MDS. The total incidence of aGVHD of any severity was 80%. Incidence of grade 3-4 aGVHD at was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%, p = 0.05) and 2-year OS (39% versus 70%, p = 0.04) compared to those who did not. The 2-year cumulative incidence of cGVHD was 44% (95% CI 28-58). CONCLUSIONS Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplant strategy up to age 70, particularly for those with advanced MDS. High incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.
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8.
Allogeneic hematopoietic stem cell transplantation with the modified myeloablative conditioning regimen for children with chronic active Epstein-Barr virus infection
Luo, Y., Wei, A., Wang, B., Zhu, G., Zhang, R., Jia, C., Yan, Y., Zhou, X., Yang, J., Qin, M., et al
Pediatric investigation. 2022;6(4):250-259
Abstract
IMPORTANCE Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only effective treatment for chronic active Epstein-Barr virus infection (CAEBV). The clinical efficacy and safety of allo-HSCT with different conditioning regimens in children with CAEBV remain unclear. OBJECTIVE To evaluate the effectiveness and safety of allo-HSCT with the modified myeloablative conditioning (MAC) regimen for children with CAEBV and also the factors affecting the outcomes. METHODS We retrospectively analyzed children with CAEBV who underwent allo-HSCT with the modified MAC regimen at Beijing Children's Hospital, Capital Medical University from October 2016 to June 2021. Data related to the clinical manifestations, engraftment, and outcome were extracted from the medical records. RESULTS The cohort comprised 41 patients (24 males, 17 females) with a median transplantation age of 92.6 (60.4, 120.7) months and a median follow-up time of 28.2 (15.3, 40.2) months. Four patients (9.8%) died, among which three died from primary disease relapse, and one died from grade IV acute graft-versus-host diseases (aGVHD) after stopping treatment. The 3-year overall survival (OS) and 3-year event-free survival (EFS) rates were 88.8% ± 5.4% and 85.0% ± 5.7%, respectively. The 3-year OS and EFS did not significantly differ between the patients with hemophagocytic lymphohistiocytosis (HLH) and the patient without HLH (87.7% ± 6.8% vs. 91.7% ± 8.0%, P = 0.790; 85.0% ± 6.9% vs. 84.6% ± 10.0%, P = 0.921), or among the patients with complete remission, partial remission, and activity disease before HSCT (all P > 0.05). Multivariate analysis showed that grade III-IV aGVHD was a risk factor for mortality (Hazards ratio: 11.65, 95% confidence interval: 1.00, 136.06; P = 0.050). INTERPRETATION Allo-HSCT with the modified MAC regimen is safe and effective for pediatric CAEBV. This treatment benefits patients with HLH or active disease. Patients with Grade III-IV aGVHD may be associated with worse outcomes.
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9.
Comparison of the impact of two post-remission therapy regimens on cardiac events in acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation
Hayakawa, J., Nakasone, H., Minakata, D., Fujiwara, S. I., Gomyo, A., Akahoshi, Y., Komiya, Y., Harada, N., Ugai, T., Kameda, K., et al
International journal of hematology. 2022;116(2):239-247
Abstract
High-dose cytarabine (HD-AraC) or anthracycline-containing chemotherapies are used as post-remission therapy for acute myeloid leukemia (AML) patients. However, it remains unclear which regimen would be better as post-remission therapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thus, we compared the incidence of cardiac events and event-free survival (EFS) after allo-HSCT at two Japanese hospitals between HD-AraC and anthracycline-containing post-remission therapy to clarify the safety of post-remission therapy. Of a total of 132 patients, 68 received HD-AraC (HD-AraC group) and 64 received anthracycline-containing chemotherapy (ANT group). HD-AraC was preferentially selected for core-binding factor AML patients (p = 0.008). The median cumulative anthracycline dose was 115.2 mg/m(2) in the HD-AraC group and 318.7 mg/m(2) in the ANT group (p < 0.0001). Cardiac events were observed in 18 (13.6%) patients during the follow-up period. The 3-year cumulative incidence of cardiac events was 9.1% in the HD-AraC group and 11.0% in the ANT group (p = 0.70). EFS at 3 years after allo-HSCT was 40.9% in the HD-AraC group and 39.6% in the ANT group (p = 0.51). In conclusion, incidence of cardiac events did not differ significantly between post-remission therapy regimens in AML patients who underwent allo-HSCT.
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10.
Radiation-free myeloablative allogeneic hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia: A comparison of outcomes between patients with and without central nervous system involvement
Esfandbod, M., Enshaei, M., Monzavi, S. M., Kabootari, M., Behfar, M., Hamidieh, A. A.
Leukemia Research. 2021;111:106703
Abstract
For patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), total body irradiation (TBI) has been particularly advocated as a part of the conditioning regimen in case of extramedullary involvement in sanctuary sites such as the central nervous system (CNS), to ensure greater tissue penetration. In resource-limited countries lacking TBI facilities; however, ALL patients undergo radiation-free myeloablative conditioning, though its impacts on post-HSCT outcomes of the patients with pre-HSCT CNS involvement have not been analyzed. In this 14-year series of 278 adult (> 18 y) ALL patients undergoing TBI-free busulfan/cyclophosphamide conditioning allo-HSCT, we found that the long-term probabilities of overall survival, disease free survival, relapse and non-relapse mortality were not significantly different between CNS-involved and CNS-spared patients. Moreover, there was no statistically significant difference in the incidence of post-HSCT CNS relapse between CNS-involved and CNS-spared patients. Pre-HSCT cranial radiation therapy (CRT) showed no significant preventive effect on the likelihood of post-HSCT CNS relapse. Through multivariable regression analysis, grade III-IV acute graft-versus-host disease (GvHD), extensive chronic GvHD and post-HSCT relapse were ascertained as independent determinants of mortality (Adj.R(2) = 53.9 %, F((12,265)) = 28.1, P < 0.001), while other parameters including Philadelphia translocation, pre-HSCT CNS involvement and CRT were found to have no independent effect. Although this study was not an attempt to compare TBI-based vs. non-TBI conditioning, the TBI-free myeloablative allo-HSCT was shown to be feasible and an option for adult ALL patients with CNS involvement, considering the comparable outcomes between patients with and without CNS involvement.