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1.
Prognostic significance of persisting DNMT3A, ASXL1, and TET2 mutation burden in acute myeloid leukemia patients with allogeneic hematopoietic stem cell transplantation during complete remission
Lai, X., Xiao, J., Wang, T., Hou, C., Chen, J., Wu, D., Xu, Y.
Leukemia & lymphoma. 2023;:1-9
Abstract
We retrospectively analyzed 155 AML patients with DAT mutations at diagnosis who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at complete remission. Of the 155 AML patients with DAT mutations at diagnosis, 59 (38.1%) patients had persisting DAT mutations pretransplantation. Compared to patients with pretransplant DAT transitions, patients with persisting DAT mutation burden were shown to be older (p = 0.004), and fewer patients had TET2 mutations at diagnosis (p = 0.033). Patients with persistent DAT mutation burden had shorter overall survival (OS) (3-year OS: 59.3% vs. 83.0%, p < 0.001) and disease-free survival (DFS) (3-year DFS: 56.1% vs. 83.0%, p < 0.001) with a higher cumulative incidence of relapse (CIR) (24.6% vs. 17.4%, p = 0.002) than those with DAT transitions. Additionally, multivariate analysis confirmed that persisting DAT mutations were an independent adverse factor for relapse, OS, and DFS. Collectively, persisting DAT mutations prior to allo-HSCT at complete remission for AML correlated with negative outcomes.
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Autologous stem cell transplantation in adult patients with intermediate-risk acute myeloid leukemia in first complete remission and no detectable minimal residual disease. A comparative retrospective study with haploidentical transplants of the global committee and the ALWP of the EBMT
Chen, J., Labopin, M., Pabst, T., Zhang, X., Jiang, E., Tucci, A., Cornelissen, J., Meijer, E., Khevelidze, I., Polge, E., et al
Bone marrow transplantation. 2023
Abstract
In patients with acute myeloid leukemia (AML) of intermediate-risk (IR) in first remission (CR1) with no measurable residual disease (MRD negative), the choice of the best consolidation is questionable. 1122 adult patients from 196 centers, transplanted in 2010-21 were analyzed: 547 received an autologous stem cell transplantation (ASCT) and 575 a Haploidentical donor transplant. Because of a significant interaction, comparisons were done separately for patients with wild-type FLT3 (FLT3-wt) and FLT3-ITD mutation (FLT3-ITD). In FLT3-wt patients, haploidentical transplants had two year lower relapse incidence (RI) (16.9% versus 32.6%; HR = 0.40, p < 0.001), higher NRM higher (17.2% vs 3.5%; HR = 7.02, p < 0.001), similar LFS (65.9% vs 63.8%; p = 0.37) and lower OS (73.2% vs 80.6%; HR = 1.69, p = 0.018). In FLT3-ITD patients, haploidentical transplants had two year lower RI (8.2% vs 47.8%; HR = 0.14, p < 0.001) higher NRM (20.2% vs 5.6%; HR = 3.43, p = 0.002), better LFS (71.5% vs 46.6%; HR = 0.53, p = 0.007) and similar OS (73.5% vs 61.9%; p = 0.44). In IR AML patients with FLT3-wt in MRD negative CR1, autologous stem cell transplantation is a valid option, while in patients with FLT3-ITD, haploidentical transplant is better. Whether autologous transplantation is superior to chemotherapy in FLT3-wt patients and the role of maintenance therapy with FLT3 inhibitors remain to be studied.
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3.
The efficacy of first salvage therapy determines the outcomes of adult patients with type 1 primary refractory acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation
Yu, Z., Yao, Y., Zhang, Y., Chen, J., Xu, Y., Xue, S., Qiu, H., Tang, X., Han, Y., Chen, S., et al
Annals of hematology. 2023
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4.
Autologous stem cell transplantation (ASCT) for acute myeloid leukemia in patients in first complete remission after one versus two induction courses: A study from the ALWP of the EBMT
Nagler, A., Galimard, J. E., Labopin, M., Blaise, D., Arcese, W., Trisolini, S. M., Wu, D., Pigneux, A., Van Gorkom, G., Rubio, M. T., et al
Cancer medicine. 2022
Abstract
BACKGROUND Achieving complete remission (CR) is the main goal in AML treatment and a prerequisite for successful autologous stem cell transplantation (ACT). METHODS Comparing results of peripheral blood ACT in patients with AML in CR1 attained following 1 versus 2 chemotherapy courses transplanted in 2000-2019. RESULTS Patients 1532 (84%) with one and 293 (16%) patients with two induction chemotherapies courses (a total of 1825 patients) were included in the study. Follow-up was 7.9 (95% CI: 7.4-8.4) and 7.7 (95% CI: 7.0-8.6) years (p = 0.8). Time from diagnosis to ACT was 4.7 (range, 3.9-5.8) versus 5.7 (range, 4.7-7.1) months (p < 0.001), respectively. Leukemia free survival (LFS) and overall survival (OS) at 5 years were inferior for patients achieving CR1 with 2 versus 1 course of chemotherapy: 26.6% versus 41.7% (HR = 1.42 [95% CI: 1.22-1.66], p < 0.001) and 36.2% versus 53.3%, (HR = 1.48 [95% CI: 1.25-1.75], p < 0.001), and 5-year relapse incidence (RI) was higher: 67.2% versus 52.3%, (HR = 1.46 [95% CI: 1.25-1.72], p < 0.001). Five-year non-relapse mortality (NRM) was 6.2% versus 6.0% for patients with 2 versus 1 chemotherapy courses, and did not differ significantly (HR = 1.31 [95% CI: 0.81-2.10], p = 0.27). CONCLUSIONS LFS and OS were inferior and relapse rate was higher in AML patients who received two inductions chemotherapy courses to reach CR1 before being autografted. AML patients who required 2 induction courses to achieve remission, may be offered allogeneic transplantation rather than an autologous one in an attempt to reduce their high RI and improve outcomes.
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5.
More than two courses of consolidation therapy pre-transplantation benefits patients with acute myeloid leukemia in the first complete remission who underwent human leukocyte antigen-matched sibling allografts: a multicenter study
Liu, J., Wu, D., Liu, Q., Chang, Y., Xu, Y., Huang, F., Huang, X., Wang, Y.
Chinese medical journal. 2022
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Abstract
BACKGROUND Although the need for consolidation chemotherapy after successful induction therapy is well established in patients with acute myeloid leukemia (AML) in first complete remission (CR1), the value of consolidation chemotherapy before allogeneic hematopoietic stem cell transplantation remains controversial. METHODS We retrospectively compared the effect of the number of pre-transplant consolidation chemotherapies on outcomes of human leukocyte antigen-matched sibling stem cell transplantation (MSDT) for patients with AML in CR1 in multicenters across China. In our study, we analyzed data of 373 AML patients in CR1 from three centers across China. RESULTS With a median follow-up of 969 days, patients with ≥ 3 courses of consolidation chemotherapy had higher probabilities of leukemia-free survival (LFS) (85.6% vs. 67.0%, P < 0.001) and overall survival (89.2% vs. 78.5%, P = 0.007), and better cumulative incidences of relapse (10.5% vs. 19.6%, P = 0.020) and non-relapse mortality (4.2% vs. 14.9%, P = 0.001) than those with ≤ 2 courses of consolidation chemotherapy. Pre-transplantation minimal residual disease-negative patients with AML in CR1 who received MSDT with ≥ 3 courses of consolidation chemotherapy had a higher probability of LFS (85.9% vs. 67.7%, P = 0.003) and a lower cumulative incidence of relapse (9.6% vs. 23.3%, P = 0.013) than those with ≤ 2 courses. CONCLUSION Our results indicate that patients with AML in CR1 who received MSDT might benefit from pre-transplant consolidation chemotherapy.
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6.
Adverse impact of a high allelic burden FLT3-ITD mutation on allogeneic hematopoietic stem cell transplantation in patients with cytogenetically normal AML
Wan, L., Ding, S., Xu, M., Lv, K., Du, Y., Wu, D., Xu, M., Liu, Y.
International journal of hematology. 2022
Abstract
Risks associated with the FLT3-ITD mutation in patients receiving chemotherapy alone for cytogenetic normal acute myeloid leukemia (CN-AML) depend on the allelic ratio (AR) and concomitant NPM1 mutation. Nevertheless, their prognostic ability after allogeneic hematopoietic cell transplantation (allo-HCT) remains undetermined. Moreover, previous studies have revealed that haploidentical transplantation improves outcomes of FLT3-ITD patients. To elucidate whether this alteration also impacts prognosis of myeloablative allo-HCT upon first remission, we retrospectively reviewed the prognostic ability of FLT3-ITD mutations in 205 CN-AML patients. Our analysis demonstrated that FLT3-ITD AR was closely related to pretransplant MRD and induction response. Multivariate analysis showed that high-AR FLT3-ITD, pretransplant MRD and induction response were independent risk factors for CN-AML. In addition, we presented evidence that the high-AR FLT3-ITD patient prognosis was not overcome by haploidentical transplantation, but was markedly improved by cGVHD. More importantly, among patients with negative pretransplant MRD, high-AR FLT3-ITD patients did not have increased relapse risk, compared to low-AR FLT3-ITD and wild-type FLT3 patients. Our findings will aid in accurate prognostic stratification of FLT3-ITD patients. We also recommend further targeted and coordinated approaches to sustain durable remission following induction chemotherapy and allo-HCT in this high-risk patient population.
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7.
Graft-Versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide versus Cyclosporine A and Methotrexate in Matched Sibling Donor Transplantation
Nagler, A., Labopin, M., Dholaria, B., Wu, D., Choi, G., Aljurf, M., Ciceri, F., Gedde-Dahl, T., Meijer, E., Niittyvuopio, R., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
Cyclosporine A and methotrexate (CSA/MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplant cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myeloid leukemia (AML). In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2-year (41.1% versus 21.3%, p=0.039) compared to CSA/MTX. The incidence of day 180 grade II-IV acute GVHD (25.2% versus 25.4%, p=0.90) and 2-year chronic GVHD (42.6% versus 42.6%, p=0.84) were comparable between PTCy and CSA/MTX, respectively. Similarly, 2-year leukemia-free survival (LFS, 54.4% versus 74.32%, p=0.052), overall survival (OS, 70.6% versus 79.7%, p=0.15) and GVHD-free-relapse-free survival (GRFS, 38.1% versus 52.5%, p=0.49) were not statistically different between PTCy versus CSA/MTX. In conclusion, GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS compared to conventional CSA/MTX in patients undergoing allo-HCT from MSD. The higher relapse observed with PTCy needs further evaluation in a prospective study.
PICO Summary
Population
Patients who underwent matched sibling donor (MSD) allogeneic transplant for acute myeloid leukemia, (AML) reported to the EBMT registry (n=1320)
Intervention
Post-transplant cyclophosphamide (PTCy, n=118)
Comparison
Cyclosporine A and methotrexate (CSA/MTX, n=1202)
Outcome
In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2-year (41.1% versus 21.3%) compared to CSA/MTX. The incidence of day 180 grade II-IV acute GVHD (25.2% versus 25.4%) and 2-year chronic GVHD (42.6% versus 42.6%) were comparable between PTCy and CSA/MTX, respectively. Similarly, 2-year leukemia-free survival (LFS, 54.4% versus 74.32%), overall survival (OS, 70.6% versus 79.7%) and GVHD-free-relapse-free survival (GRFS, 38.1% versus 52.5%) were not statistically different between PTCy versus CSA/MTX. In conclusion, GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS compared to conventional CSA/MTX in patients undergoing allo-HCT from MSD. The higher relapse observed with PTCy needs further evaluation in a prospective study.
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Allogeneic hematopoietic stem cell transplantation could improve the survival of acute myeloid leukemia patients with ASXL1 mutations
Zhou, L., An, J., Hou, C., Ding, Z., Qiu, H., Tang, X., Sun, A., Chen, S., Xu, Y., Liu, T., et al
Hematology (Amsterdam, Netherlands). 2021;26(1):340-347
Abstract
Objective: To discover the function of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in ASXL1-mutated acute myeloid leukemia (AML) patients.Methods: We analyzed the prognostic value of ASXL1 mutations and explored the role of allo-HSCT in 581 AML patients.Results: According to the definition of intermediate- and adverse-risk AML groups in the European Leukemia Net (ELN), ASXL1-mutated patients had shorter OS and DFS than ASXL1-wild-type patients in the intermediate- and adverse-risk AML groups (3-year OS: 47.5% vs. 60.8%, P<0.001; 3-year DFS: 28.5% vs. 48.9%, P<0.001). Among the cytogenetically normal acute myeloid leukemia (CN-AML), differences were found in both OS (47.4% vs.65.2%, P<0.001) and DFS (21.0% vs. 52.1%, P<0.001) between ASXL1-mutated patients and ASXL1 wild-type patients.In the ASXL1-mutated AML cohort, the patients received allo-HSCT had longer 3-year OS (P=0.0005) and 3-year DFS (P<0.0001) than those who did not receive allo-HSCT. Multivariate analysis revealed that ASXL1 mutation was an independent prognostic factor for OS (HR 2.248, 95% CI 1.155-4.375, P=0.017), and allo-HSCT had a positive impact on OS (HR 7.568, 95% CI 3.597-15.92, P<0.001) and DFS (HR 2.611, 95% CI 1.688-4.039, P<0.001) in ASXL1-mutated patients.Conclusion: The results indicate that the presence of ASXL1 mutations is a factor predictive of poor prognosis in AML patients and allo-HSCT could improve the survival of AML patients with ASXL1 mutations.
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Low-dose decitabine as part of a modified Bu-Cy conditioning regimen improves survival in AML patients with active disease undergoing allogeneic hematopoietic stem cell transplantation
Tang, X., Valdez, B. C., Ma, Y., Zhang, Q., Qu, C., Dai, H., Yin, J., Li, Z., Xu, T., Xu, Y., et al
Bone marrow transplantation. 2021
Abstract
Relapse is the major cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Effective preventive intervention in high-risk AML may be crucial. In this study, we investigated the clinical efficacy and safety of low dose decitabine (DAC) as part of a modified Busulfan-Cyclophosphamide (Bu-Cy) regimen for high-risk AML patients undergoing allo-HSCT to reduce relapse rate. Fifty-nine patients received DAC (20?mg/m(2)/d, i.v.) for 5 days, followed by modified Bu-Cy (DAC group). A matched-pair control (CON) group of 177 patients (matched 1:3) received modified Bu-Cy only. The differences were more substantial among patients with active disease: 2-year OS, 80.7% (DAC) versus 43.5% (CON), P?=?0.011 and 2-year LFS, 64.9% (DAC) versus 39.2% (CON), P?=?0.024. Median time to relapse was 8 months (DAC) versus 5 months (CON) for the entire groups and 6.5 months (DAC) versus 3.5 months (CON) for patients with active disease. In summary, our data indicated that the conditioning regimen containing low dose DAC may confer a survival advantage in high-risk AML patients with active disease undergoing allo-HSCT, and a prospective randomized trial is warranted to confirm these observations.
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Allogeneic Hematopoietic Stem Cell Transplantation Improved Survival for Adult Core Binding Factor Acute Myelogenous Leukemia Patients with Intermediate- and Adverse-Risk Genetics in the 2017 European LeukemiaNet
Wang, T., Chen, S., Chen, J., Liu, T., Zhang, T., Qiu, H., Sun, A., Chen, S., Wu, D., Xu, Y.
Transplantation and cellular therapy. 2021;27(2):173.e1-173.e9
Abstract
The use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for consolidation therapy in patients with core binding factor (CBF) acute myelogenous leukemia (AML) with intermediate- and adverse-risk genetics remains controversial. We retrospectively analyzed the clinical outcomes of 286 CBF-AML patients with intermediate- and adverse-risk genetics in first complete remission following consolidation with chemotherapy (n = 122), auto-HSCT (n = 27), or allo-HSCT (n = 137) between January 2009 and December 2018 at our center. Patients with allo-HSCT showed superior 5-year overall survival (OS; 74% versus 38% or 49%; P < .001) and progression-free survival (PFS; 74% versus 26% or 49%; P < .001) and lower cumulative incidence of relapse (CIR; 9% versus 69% or 31%; P < .001) compared with chemotherapy alone or auto-HSCT. In the allo-HSCT group, minimal residual disease (MRD) at the second and third months after allo-HSCT could predict relapse in t(8;21) patients (2 months: P(CIR) = .002; 3 months: P(CIR) < .001) but not in inv(16) patients. Moreover, positive MRD after 2 courses of consolidation chemotherapy before allo-HSCT was an independent risk factor for survival in CBF-AML patients with intermediate- and adverse-risk genetics, whereas haploidentical donor (haplo-) HSCT could overcome the adverse prognosis (5-year OS, 87%; 5-year PFS, 81%; 5-year CIR, 7%). Allo-HSCT could be the optimal first-line consolidation therapy for patients with intermediate- and adverse-risk genetics, and haplo-HSCT could improve survival for patients with positive MRD after 2 courses of consolidation chemotherapy.