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Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission
Zhao, X., Xu, Z., Li, Z., Zhou, X., Hu, Y., Wang, H.
Cancer medicine. 2024
Abstract
PURPOSE Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. METHODS Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. RESULTS In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. CONCLUSION This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.
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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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3.
The impacts of total body irradiation on umbilical cord blood hematopoietic stem cell transplantation
Wang, H., Berger, K. N., Miller, E. L., Fu, W., Broglie, L., Goldman, F. D., Konig, H., Lim, S. J., Berg, A. S., Talano, J. A., et al
Therapeutic advances in hematology. 2023;14:20406207231170708
Abstract
BACKGROUND Umbilical cord blood hematopoietic stem cells are commonly used for hematopoietic system reconstitution in recipients after umbilical cord blood transplantation (UCBT). However, the optimal conditioning regimen for UCBT remains a topic of debate. The exact impact of total body irradiation (TBI) as a part of conditioning regimens remains unknown. OBJECTIVES The aim of this study was to evaluate the impacts of TBI on UCBT outcomes. DESIGN This was a multi-institution retrospective study. METHODS A retrospective analysis was conducted on the outcomes of 136 patients receiving UCBT. Sixty-nine patients received myeloablative conditioning (MAC), in which 33 underwent TBI and 36 did not, and 67 patients received reduced-intensity conditioning (RIC), in which 43 underwent TBI and 24 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in the MAC subgroup and RIC subgroup, respectively. RESULTS In the RIC subgroup, patients who underwent TBI had superior overall survival (adjusted hazard ratio [aHR] = 0.25, 95% confidence interval [CI]: 0.09-0.66, p = 0.005) and progression-free survival (aHR = 0.26, 95% CI: 0.10-0.66, p = 0.005). However, in the MAC subgroup, there were no statistically significant differences between those receiving and not receiving TBI. CONCLUSION In the setting of RIC in UCBT, TBI utilization can improve overall survival and progression-free survival. However, TBI does not show superiority in the MAC setting.
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4.
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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5.
Unique reduced intensity conditioning haploidentical peripheral blood stem cell transplantation protocol for patients with hematological malignancy
Xu, J., Miao, W., Yuan, H., Liu, Y., Chen, G., Wang, H., Aizezi, G., Qu, J., Duan, X., Yang, R., et al
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
Reduced-intensity conditioning haploid hematopoietic stem cell transplantation (RIC-haplo-HSCT) requires more hematopoietic progenitor and stem cells (HPSCs) to promote engraftment and immune reconstitution and needs stronger graft versus leukemia (GVL) effect. Peripheral blood stem cells (PBSCs) offer more advantages compared to bone marrow (BM). However, higher dose non-T cell depleted (non-TCD) in vitro PBSCs may increase the occurrence of severe graft versus host disease (GVHD). This prospective, single-arm clinical research was performed to investigate high-dose non-TCD in vitro PBSCs as graft, Flu/Ara-C/Bu (FAB) as conditioning regimen, adopting rATG to remove T cells in vivo, and enhancing GVHD prophylaxis with IL-2 receptor antagonist in RIC-haplo-HSCT in patients with hematological malignancies aged 50 to 70 years or < 50 years with comorbidities (HCT-CI scores ≥2) classified as intermediate to higher risk. The primary endpoint was day-100 acute GVHD (aGVHD). A total of 47 patients were enrolled; the median age was 52 years (range: 30-68 years), the median follow-up time was 34 months (range: 2-99), and the medium-infused doses of MNC, CD34+ cells, and CD3+ cells were 15.93 × 10(8)/kg, 8.68 × 10(6)/kg and 5.57 × 10(8)/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day-100 was 30.3% (95% CI: 15.9-44.8), while that of grade III-IV aGVHD was 10.2% (95% CI: 0.6-19.8). The two-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI: 19.0-50.8). The two-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI: 11.80-40.40) and 8.7% (95% CI: 3.26-20.65), respectively. The two-year cumulative incidence of relapse was 17.3% (95% CI: 5.1-29.5). The two-year overall survival and disease-free survival rates were 71.2% (95% CI: 57.9-84.5) and 66.2% (95% CI: 52.1-80.3), respectively. The outcomes showed that the incidence of aGVHD was not high, and the overall efficacy was good. This study demonstrated that this unique RIC-haplo-PBSCT protocol was effective in treating hematological malignancies. Nonetheless, larger prospective multi-center clinical trials and experimental studies should be performed to further confirm our findings.
PICO Summary
Population
Adults with haematological malignancies aged 50 to 70 years or less than 50 years but with intermediate or higher risk comorbidities (HCT-CI scores ≥2), from a single centre in China (n=47)
Intervention
Reduced intensity conditioning haploidentical HSCT: high-dose non-T-cell depleted in vitro peripheral blood stem cells as graft, Flu/Ara-C/Bu (FAB) as conditioning regimen, rabbit antithymocyte globulin (rATG) to remove T cells in vivo, and enhanced GVHD prophylaxis with IL-2 receptor antagonist.
Comparison
None
Outcome
The median age was 52 years (range: 30-68 years), the median follow-up time was 34 months (range: 2-99), and the medium-infused doses of MNC, CD34+ cells, and CD3+ cells were 15.93 × 10(8)/kg, 8.68 × 10(6)/kg and 5.57 × 10(8)/kg, respectively. The cumulative incidence of grade II-IV aGVHD at day-100 was 30.3% (95% CI: 15.9-44.8), while that of grade III-IV aGVHD was 10.2% (95% CI: 0.6-19.8). The two-year cumulative incidence of chronic GVHD (cGVHD) was 34.9% (95% CI: 19.0-50.8). The two-year cumulative incidences of localized and extensive cGVHD were 26.1% (95% CI: 11.80-40.40) and 8.7% (95% CI: 3.26-20.65), respectively. The two-year cumulative incidence of relapse was 17.3% (95% CI: 5.1-29.5). The two-year overall survival and disease-free survival rates were 71.2% (95% CI: 57.9-84.5) and 66.2% (95% CI: 52.1-80.3), respectively.
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Decitabine-Intensified Modified Busulfan/Cyclophosphamide Conditioning Regimen Improves Survival in Acute Myeloid Leukemia Patients Undergoing Related Donor Hematopoietic Stem Cell Transplantation: A Propensity Score Matched Analysis
Li, Z., Shi, W., Lu, X., Lu, H., Cao, X., Tang, L., Yan, H., Zhong, Z., You, Y., Xia, L., et al
Frontiers in oncology. 2022;12:844937
Abstract
To identify the benefit of decitabine (Dec)-intensified myeloablative conditioning on the outcomes of patients with acute myeloid leukemia (AML) after related donor hematopoietic stem cell transplantation (HSCT), we performed a retrospective matched-pair study from a pool of 156 patients to evaluate Dec [20 mg/m(2)/day intravenously (i.v.) on days -11 to -7]-intensified modified busulfan/cyclophosphamide (mBuCy) conditioning regimen vs. mBuCy regimen in 92 AML patients, with 46 patients in each cohort. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was lower in the Dec group (15.2% ± 0.3% vs. 32.6% ± 0.5%, P = 0.033). Compared with mBuCy group (15.5% ± 0.3%), a significantly higher proportion of limited chronic GVHD (cGVHD) in Dec group (35% ± 0.6%) was observed (P = 0.025). Dec-intensified mBuCy conditioning was associated with better 2-year overall survival (OS) and GVHD-free relapse-free survival (GRFS) (81% ± 6.2% vs. 59.4% ± 7.5%, P = 0.03; 58.7% ± 8.1% vs. 40.9% ± 7.3%, P = 0.042; respectively). Our results also elucidated that the Dec group had better 2-year OS and lower 2-year cumulative incidence of relapse (CIR) in patients acquiring haploidentical HSCT than that of the mBuCy group (84.8% ± 7.1% vs. 58.2% ± 10.3%, P = 0.047; 17.9% ± 0.8% vs. 40.0% ± 1.0%, P = 0.036; respectively), which did not increase the treatment-related mortality and regimen-associated toxicities. Dec-intensified myeloablative regimen and high-risk stratification were the variables associated with OS, leukemia-free survival (LFS), and GRFS in multivariate analysis. In high-risk patients, no differences were found in CIR, OS, LFS, and GRFS between the two groups. These data indicated that Dec-intensified mBuCy conditioning regimen was associated with better survival than mBuCy regimen in AML patients, especially in patients undergoing haploidentical HSCT.
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7.
[Study on Application of RVD Regimen Sequential Auto-HSCT in the Treatment of Multiple Myeloma Evaluated by Propensity Score Matching]
Wang, Y., Xue, Y., Fu, C. M., Feng, K., Li, X. L., Duan, Y. Y., Zhang, C. X., Yang, Y. J., Shi, H., Fu, J., et al
Zhongguo shi yan xue ye xue za zhi. 2022;30(4):1150-1155
Abstract
OBJECTIVE To investigate the application effect of sequential autologous hematopoietic stem cell transplantation (Auto-HSCT) with lenalidomide, bortezomib and dexamethasone (RVD) in the treatment of multiple myeloma (MM) evaluated by propensity score matching. METHODS The clinical data of 49 MM patients treated with RVD scheme and followed-up for 36 months in the hospital from January 2015 to January 2021 were retrospectively analyzed and included in the control group, the clinical data of 54 MM patients who received RVD scheme and sequential Auto-HSCT scheme and completed 36 months of follow-up in the hospital during the same period were collected and included in the observation group. PSM method (1∶1, caliper value=0.01) was used to match the control group with the observation group based on baseline data and laboratory indexes, covariate equilibrium samples were obtained between groups (40 cases in each group). The clinical efficacy of patients in the two groups after 18 weeks of treatment was compared; the incidence of toxic and side effects during treatment of patients in the two groups was compared; the survival of patients in the two groups was compared after 36 months of follow-up. RESULTS The ORR and DCR in the observation group were higher than those in the control group, the difference was statistically significant (P<0.05). Compared the incidence of fatigue, rash, thrombocytopenia, anemia and nausea of patients in the two groups, there was no statistical significant difference (P>0.05). After 36 months of follow-up (no loss during follow-up), 4 cases died from illness in the observation group, with a survival rate of 90% and an average survival time of 35.61 (95% CI: 35541-35.685) months, 10 cases died from illness in the control group, with a survival rate of 75% and an average survival time of 34.70 (95% CI: 34.559-34.832) months, the survival rate of the observation group was higher than that of the control group, the difference was statistically significant (P<0.05). CONCLUSION Sequential Auto-HSCT with RVD regimen in the treatment of MM can improve the short-term efficacy and increase the survival rate of patients, which will not increase toxic and side effects and has high safety.
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8.
Unmanipulated haploidentical haematopoietic cell transplantation with radiation-free conditioning in Fanconi anaemia: A retrospective analysis from the Chinese Blood and Marrow Transplantation Registry Group
Xu, L., Lu, Y., Hu, S., Li, C., Tang, Y., Wang, H., Yan, J., Chen, J., Liu, S., Sun, Y., et al
British journal of haematology. 2022
Abstract
Haematopoietic cell transplantation (HCT) is the only curative treatment for haematological complications in patients with Fanconi anaemia (FA). Haploidentical (haplo-) HCT is a promising alternative for FA. We aimed to analyse the outcomes of unmanipulated haplo-HCT in patients with FA with radiation-free conditioning. A total of 56 patients from 11 centres between 2013 and 2021 in China were retrospectively analysed. The mean (SD) cumulative incidence was 96.4% (0.08%) for 30-day neutrophil engraftment and 85.5% (0.24%) for 100-day platelet engraftment. With a median (range) follow-up of 2.4 (0.2-5.8) years, favourable mean (SD) overall survival of 80.9% (5.5%) and event-free survival of 79.3% (5.6%) were achieved. The mean (SD) incidences of acute graft-versus-host disease (aGvHD) Grade II-IV and Grade III-IV were 55.4% (0.45%) and 42.9 (0.45%) respectively. The mean (SD) cumulative incidence of 3-year chronic graft-versus-host disease (cGvHD) was 34.7% (0.86%) and that of moderate-to-severe cGvHD was 9.0% (0.19%). Our data demonstrate that in unmanipulated haplo-HCT for patients with FA, radiation-free regimens based on fludarabine and low-dose cyclophosphamide ± busulfan achieved favourable engraftment and survival with relatively high incidences of aGvHD and cGvHD. These results prompt the use of low-intensity conditioning without radiation and intensive GvHD prophylaxis when considering unmanipulated haplo-HCT in patients with FA.
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9.
ABO incompatibility does not affect transfusion requirements or clinical outcomes of unrelated cord blood transplantation after myeloablative conditioning for haematological malignancies
Chen, Y., Wan, X., Cao, Y., Wang, H., Han, D., Zhang, Y., Yao, W., Song, K., Fan, Q., Zhu, X., et al
Blood transfusion = Trasfusione del sangue. 2021
Abstract
BACKGROUND The effects of ABO incompatibility on cord blood transplantation (CBT) have not been confirmed. We retrospectively investigated the effect of ABO incompatibility on the clinical outcomes and changes of isoagglutinin titres of 261 consecutive patients who underwent CBT in a single centre. MATERIAL AND METHODS We studied patients with haematological malignancies undergoing unrelated CBT following myeloablative conditioning. There were 80 matched, 72 major mismatched, 72 minor mismatched, and 37 bidirectional mismatched transplants. Risk factors that could potentially influence the patients' outcomes were evaluated. Immunoglobulin M (IgM) isohaemagglutinin antibody (IHA) titres were determined 1 day before and 2, 4, 6 and 8 weeks after the transplant. RESULTS ABO mismatches did not influence engraftment, transfusion requirements, event-free survival or overall survival following CBT. The anti-donor IgM serum IHA titres fell to =1:8 at week 8 after CBT in all patients with ABO major and bidirectional mismatches. The percentages of patients requiring platelet and red blood cell transfusions in the period 31-61 days after CBT were markedly lower than in the period 0-30 days after CBT, being 15% vs 99% for platelets and 23% vs 78% for red blood cells, respectively. Of the 69 recipients of minor mismatched CBT tested, only three with AB blood type developed low titres of anti-recipient IHA after 5 months. DISCUSSION In this study ABO incompatibility did not affect clinical outcomes after CBT. A higher number of CD34(+) cells infused was correlated with earlier engraftment. Severe acute graft-versus-host disease was associated with poor overall survival. As the IHA titre decreased, so did the number of patients requiring blood transfusion. Rapidly decreasing anti-donor IHA titres and the non-production of donor anti-recipient A and/or B antibodies might contribute to a good outcome of ABO-incompatible CBT with myeloablative conditioning for haematological malignancies.
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10.
Pre-transplant therapy for patients with myelodysplastic syndromes: A systematic review and meta-analysis
Wang, H., Li, Y., Zhou, W., Wang, R., Li, Y., Yu, L.
Leukemia research. 2021;110:106645
Abstract
BACKGROUND The value of pre-transplant cytoreductive therapy for patients with myelodysplastic syndromes (MDS) is controversial. Here, we conducted a meta-analysis to explore the effects of cytoreduction before transplantation. METHODS PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies comparing post-transplant outcomes in MDS patients receiving different pre-transplant therapy. Pooled hazard ratios (HRs) and 95 % confidence intervals (CI) were calculated. RESULTS Eighteen reports were included. Post-transplant outcomes were similar for MDS patients receiving pre-transplant cytoreductive therapy and upfront transplantation in terms of overall survival (OS: HR, 0.92; 95 % CI, 0.79-1.07), relapse-free survival (RFS: HR, 1.18; 95 % CI, 0.94-1.47), cumulative incidence of relapse (CIR: HR, 1.08; 95 % CI, 0.88-1.33), and non-relapse mortality (NRM: HR, 0.93; 95 % CI, 0.74-1.18). Pre-transplant hypomethylating agents (HMAs) and chemotherapy were not different regarding post-transplant OS, RFS, CIR, and NRM. Achieving complete remission (CR) before transplantation was associated with increased RFS (HR, 0.80; 95 %CI, 0.63-1.00) and decreased NRM (HR, 0.53; 95 % CI, 0.32-0.90) when compared with upfront transplantation. CONCLUSIONS Timely transplantation is of great value for MDS patients. Suitable pre-transplant cytoreduction could be used during the search for donors.