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Impact of measurable residual disease on outcomes of unrelated donor haematopoietic cell transplantation with post-transplant cyclophosphamide in AML in first complete remission
Nagler, A., Labopin, M., Dholaria, B., Blaise, D., Bondarenko, S., Vydra, J., Choi, G., Rovira, M., Reményi, P., Meijer, E., et al
British journal of haematology. 2023
Abstract
Pre-transplant measurable residual disease (MRD) predicts relapse and outcome of allogeneic haematopoietic cell transplantation (allo-HCT). The impact of MRD on the outcomes of post-transplant cyclophosphamide (PTCy)-based allo-HCT from a matched unrelated donor (UD) is unknown. This study assessed the impact of MRD in acute myeloid leukaemia (AML) in the first complete remission (CR1). A total of 272 patients (MRD negative [MRD-], n = 165; MRD positive [MRD+], n = 107) with a median follow-up of 19 (range: 16-24) months were studied. The incidence of grades II-IV and grades III-IV acute GVHD at day 180 was 25.2% and 25% (p = 0.99), and 10.6% and 6.8% (p = 0.29), respectively, and 2-year chronic GVHD was 35% and 30.4% (p = 0.96) in MRD+ and MRD- cohorts, respectively. In multivariate analysis, MRD+ status was associated with a higher incidence of relapse (RI) (hazard ratio [HR] = 2.56, 95% CI: 1.39-4.72), lower leukaemia-free survival (LFS) (HR = 2.04, 95% CI: 1.23-3.39), overall survival (OS) (HR = 1.83, 95% CI: 1.04-3.25) and GVHD-free, relapse-free survival (GRFS) (HR = 1.69, 95% CI: 1.10-2.58). MRD status did not have a significant impact on non-relapse mortality (NRM), or acute or chronic GVHD risk. Among patients with AML undergoing UD allo-HCT with PTCy, pre-transplant MRD+ status predicted a higher relapse rate, lower LFS, OS and GRFS.
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2.
Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) in second complete remission (CR2) transplanted from unrelated donors with post-transplant cyclophosphamide (PTCy). A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Nagler, A., Labopin, M., Swoboda, R., Kulagin, A., Labussière-Wallet, H., Rovira, M., Blaise, D., Vydra, J., Yakoub-Agha, I., Choi, G., et al
Bone marrow transplantation. 2023
Abstract
Post-transplant cyclophosphamide (PTCy) is being increasingly used as graft-versus-host disease (GVHD) prophylaxis post allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) transplanted in first complete remission (CR1). However, results may differ in patients transplanted in CR2. We retrospectively evaluated transplant outcomes of adult AML patients transplanted between 2010-2019 from 9-10/10 human leukocyte antigen (HLA)-matched unrelated donor (UD) in CR2. In total, 127 patients were included (median age 45.5 years, 54% male). Median follow-up was 19.2 months. Conditioning was myeloablative (MAC) in 50.4% and the graft source was peripheral blood in 93.7% of the transplants. Incidence of acute (a)GVHD II-IV and III-IV was 26.2% and 9.2%. Two-year total and extensive chronic (c)GVHD were 34.3% and 13.8 %, respectively. Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were 17.2%, 21.1%, 61.7, %, 65.2%, and 49.3%, respectively. Time from diagnosis to transplant (>18 months) was a favorable prognostic factor for RI, LFS, OS, and GRFS while favorable risk cytogenetics was a positive prognostic factor for OS. The patient's age was a poor prognostic factor for NRM and cGVHD. Finally, the female-to-male combination and reduced intensity conditioning (RIC) were poor and favorable prognostic factors for cGVHD, respectively. We conclude that PTCy is an effective method for GVHD prophylaxis in AML patients undergoing allo-HCT in CR2 from UD.
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Prediction of Nonrelapse Mortality in Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation With Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis
Hermans, S. J. F., Versluis, J., Labopin, M., Giebel, S., van Norden, Y., Moiseev, I., Blaise, D., Díez Martín, J. L., Meijer, E., Rovira, M., et al
HemaSphere. 2023;7(3):e846
Abstract
Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.
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4.
Comparison of outcomes after unrelated double-unit cord blood and haploidentical peripheral blood stem cell transplantation in adults with acute myeloid leukemia, a study on behalf of Eurocord and ALWP-EBMT
Ruggeri, A., Galimard, J. E., Labopin, M., Rafii, H., Blaise, D., Ciceri, F., Diez-Martin, J. L., Cornelissen, J., Chevallier, P., Sanchez-Guijo, F., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Unmanipulated haploidentical stem cell transplantation with post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis (Haplo-PTCY) and unrelated double-unit umbilical cord blood transplant (dUCBT) are feasible options to treat patients with high risk acute myeloid leukemia (AML). OBJECTIVES The aim of our study was to compare outcomes after dUCBT and Haplo-HCT using PBSC in adult patients with AML in complete remission (CR) transplanted in European Society for Blood and Marrow Transplantation (EBMT) affiliated centers. STUDY DESIGN In a population of adults with de novo AML in first or second CR, we compared outcomes after dUCBT (n=165) and after Haplo-PTCY PBSC (n=544) performed between January 2013 and December 2018. Patients receiving in-vivo antithymocyte globuline (ATG), Campath, or ex-vivo T-cell depletion were excluded. RESULTS Median follow-up was 33 months for Haplo-PTCY and 52 months for dUCBT. No statically significant differences were observed between the two approaches in grade-II-IV acute-GVHD (hazard ratio [HR]=1.31, p=0.18), and grade-III-IV (HR=1.17, p=0.56) or in chronic-GVHD (HR=0.86, p=0.48) or relapse (HR=1.07, p=0.77), non-relapse mortality (NRM; HR=0.94, p=0.77), leukemia-free survival (LFS; HR=0.99, p=0.95) and overall survival (OS; HR=0.99, p=0.97) when comparing dUCBT with Haplo-PTCY. Favourable cytogenetic risk was the only factor predictive of lower relapse incidence. Younger age at transplant was associated with lower NRM and higher LFS and OS. CONCLUSION Both dUCBT and Haplo-PTCY with PBSC can be considered as valid approaches for adult AML patients in complete remission. New strategies should be investigated in both settings to define the most appropriate conditioning regimen and potentially, to decrease relapse incidence and NRM through better immune reconstitution and optimal supportive care.
PICO Summary
Population
Adults with acute myeloid leukaemia having first allogeneic transplant, and reported to the EBMT or Eurocord registries (n=709)
Intervention
Double cord blood transplantation (dUCBT, n=165)
Comparison
Haploidentical transplant with post-transplant cyclophosphosphamide (Haplo-PTCY, n=544)
Outcome
No statistically significant differences were observed between the two approaches in grade-II-IV acute-GVHD (hazard ratio [HR]=1.31), and grade-III-IV (HR=1.17) or in chronic-GVHD (HR=0.86) or relapse (HR=1.07), non-relapse mortality (NRM; HR=0.94), leukemia-free survival (LFS; HR=0.99) and overall survival (OS; HR=0.99) when comparing dUCBT with Haplo-PTCY. Favourable cytogenetic risk was the only factor predictive of lower relapse incidence. Younger age at transplant was associated with lower NRM and higher LFS and OS.
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Long-term outcomes in patients with relapsed/refractory acute myeloid leukemia and other high-risk myeloid malignancies after undergoing sequential conditioning regimen based on IDA-FLAG and high-dose melphalan
Guijarro, F., Bataller, A., Diaz-Beyá, M., Garrido, A., Coll-Ferrà, C., Vives, S., Salamero, O., Valcárcel, D., Tormo, M., Arnan, M., et al
Bone marrow transplantation. 2022
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) remains the only curative option for relapsed/refractory acute myeloid leukemia and other high-risk myeloid malignancies. To improve alloHCT results in this setting, sequential regimens were designed as a strategy to lower tumor burden and quickly induce the graft-versus-leukemia effect. We analyzed long-term outcomes of a sequential regimen based on IDA-FLAG and high-dose melphalan, as set forth by the CETLAM cooperative group. This protocol yielded a high complete response rate (89%) and a lower cumulative relapse incidence (30% at five years) compared to other regimens. Five-year non-relapse mortality, however, reached 45%, with grade 3-4 acute graft-versus-host disease being the most frequent adverse event (a 100-day incidence of 29%). Altogether, 5-year overall survival was 25% in this group of patients with otherwise dismal prognosis. Long-term survivors enjoyed a good quality of life after a median follow-up of 68 months.
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Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT
Spyridonidis, A., Labopin, M., Brissot, E., Moiseev, I., Cornelissen, J., Choi, G., Ciceri, F., Vydra, J., Reményi, P., Rovira, M., et al
Bone marrow transplantation. 2022
Abstract
In this registry-based study which includes acute myeloid leukemia patients who underwent a matched unrelated donor allogeneic peripheral-blood stem cell transplantation in complete remission and received post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GvHD) prophylaxis, we compared 421 recipients without anti-thymocyte globulin (ATG) with 151 patients with ATG. The only significant differences between PTCY and PTCY + ATG cohorts were the median year of transplant and the follow-up period (2017 vs 2015 and 19.6 vs 31.1 months, respectively, p < 0.0001). Overall, 2-year survival was 69.9% vs 67.1% in PTCY and PTCY + ATG, respectively, with deaths related to relapse (39% vs 43.5%), infection (21.9% vs 23.9%) or GvHD (17.1% vs 17.4%) not differing between groups. On univariate comparison, a significantly lower rate of extensive chronic GvHD was found when ATG was added (9.9% vs 21%, p = 0.029), a finding which was not confirmed in the multivariate analysis. The Cox-model showed no difference between PTCY + ATG and PTCY alone with respect to acute and chronic GvHD of all grades, non-relapse mortality, relapse, leukemia-free survival, overall survival, and GvHD-free-relapse-free survival between study cohorts. Our results highlight that the addition of ATG in PTCY does not provide any extra benefit in terms of further GvHD reduction, better GRFS or better survival.
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Additional cytogenetic features determines outcome in patients allografted for TP53 mutant acute myeloid leukemia
Loke, J., Labopin, M., Craddock, C., Cornelissen, J. J., Labussière-Wallet, H., Wagner-Drouet, E. M., Van Gorkom, G., Schaap, N. P. M., Kröger, N. M., Veelken, J. H., et al
Cancer. 2022
Abstract
BACKGROUND The presence of TP53 mutations is associated with an unfavorable outcome in patients allografted for acute myeloid leukemia (AML), leading some to question the benefit of an allogeneic stem cell transplantation (allo-SCT) for this patient group, although this has not been studied in a large cohort. METHODS A total of 780 patients with AML in first complete remission, with either intermediate- or adverse-risk cytogenetics, whose TP53 mutation status was reported, were included in this study from the European Society for Blood and Marrow Transplantation. RESULTS Two-year overall survival (OS) was impaired in patients (n = 179) with evidence of a TP53 mutation at diagnosis (35.1%; 95% confidence interval [CI], 26.7-43.7) as compared to the cohort without (n = 601) (64%; 95% CI, 59.1-68.4; P = .001). In patients with mutant TP53 AML with no evidence of either chromosome 17p loss (17p-) and/or complex karyotype (CK) (n = 53, 29.6%), 2-year OS was 65.2% (95% CI, 48.4-77.6). This was not significantly different to patients without TP53 mutations. In patients with mutant TP53 AML with either 17p- and/or CK (n = 126, 70.4%), the OS was lower (24.6%; 95% CI, 16.2-34; P = .001). CONCLUSIONS In summary, the adverse prognostic effect of TP53 mutations in AML following an allo-SCT is not evident in patients with neither co-occurring 17p- and/or CK, and these data inform decisions regarding allo-SCT in patients with TP53 mutant AML.
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Allogeneic stem cell transplantation for AML patients with RUNX1 mutation in first complete remission: a study on behalf of the acute leukemia working party of the EBMT
Waidhauser, J., Labopin, M., Esteve, J., Kröger, N., Cornelissen, J., Gedde-Dahl, T., Van Gorkom, G., Finke, J., Rovira, M., Schaap, N., et al
Bone marrow transplantation. 2021
Abstract
Acute myeloid leukemia with runt-related transcription factor 1 gene mutation (RUNX1+ AML) is associated with inferior response rates and outcome after conventional chemotherapy. We performed a retrospective, registry-based analysis to elucidate the prognostic value of RUNX1 mutation after allogeneic stem cell transplantation (alloSCT). All consecutive adults undergoing alloSCT for AML in first complete remission (CR1) between 2013 and 2019 with complete information on conventional cytogenetics and RUNX1 mutational status were included. Endpoints of interest were cumulative relapse incidence, non-relapse mortality, overall and leukemia-free survival (OS/LFS), and GvHD-free/relapse-free survival. A total of 674 patients (183 RUNX1+, 491 RUNX1-) were identified, with >85% presenting as de novo AML. Median follow-up was 16.4 (RUNX1+) and 21.9 (RUNX1-) months. Survival rates showed no difference between RUNX1+ and RUNX1- patients either in univariate or multivariate analysis (2-year OS: 67.7 vs. 66.1%, p?=?0.7; 2-year LFS: 61.1 vs. 60.8%, p?=?0.62). Multivariate analysis identified age, donor type and poor cytogenetics as risk factors for inferior outcome. Among patients with RUNX+ AML, older age, reduced intensity conditioning and minimal residual disease at alloSCT predicted inferior outcome. Our data provide evidence that the negative influence of RUNX1 mutations in patients with AML can be overcome by transplantation in CR1.
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Total body irradiation + fludarabine compared to busulfan + fludarabine as "reduced-toxicity conditioning" for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT
Giebel, S., Labopin, M., Sobczyk-Kruszelnicka, M., Stelljes, M., Byrne, J. L., Fegueux, N., Beelen, D. W., Rovira, M., Spyridonidis, A., Blaise, D., et al
Bone marrow transplantation. 2020
Abstract
The optimal conditioning for patients with acute myeloid leukemia in first complete remission treated with allogeneic hematopoietic cell transplantation (allo-HCT) has not been defined so far. In this retrospective study, we compared two "reduced-toxicity" regimens: intravenous busulfan at a total dose of 9.6?mg/kg (3 days)?+?fludarabine (Bu3/Flu) and total body irradiation at a dose of 8?Gy?+?fludarabine (TBI8Gy/Flu). In the entire study cohort (n?=?518), the probabilities of overall survival (OS), leukemia-free survival (LFS), relapse and non-relapse mortality (NRM) at 2 years for Bu3/Flu and TBI8Gy/Flu were 62% vs. 72.5% (p?=?0.051), 59.5% vs. 65% (p?=?0.15), 30% vs. 20% (p?=?0.01), and 10% vs. 14% (p?=?0.18), respectively. In multivariate model for patients <50 years old, TBI8Gy/Flu was associated with improved LFS (hazard ratio (HR)?=?0.5, p?=?0.04), OS (HR?=?0.31, p?=?0.004), and survival free from both graft-versus-host disease and relapse (HR?=?0.55, p?=?0.03), as well as tendency to reduced risk of relapse (HR?=?0.53, p?=?0.08). Among patients aged 50 years or older the use of TBI8Gy/Flu was associated with increased incidence of NRM (HR?=?3.9, p?=?0.0009), with no significant impact on other outcome measures. We conclude that the use of TBI8Gy/Flu as "reduced-toxicity" regimen may be advised in younger patients with AML referred for allo-HCT.
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Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT
Sanz, J., Galimard, J. E., Labopin, M., Afanasyev, B., Angelucci, E., Ciceri, F., Blaise, D., Cornelissen, J. J., Meijer, E., Diez-Martin, J. L., et al
Journal of hematology & oncology. 2020;13(1):46
Abstract
BACKGROUND The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy. METHODS We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n = 215), MUD (n = 235), and Haplo (n = 789) donors registered in the EBMT database between 2010 and 2017. RESULTS The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II-IV GVHD (HR 1.6; 95% CI 1.1-2.4) and NRM (HR 2.6; 95% CI 1.5-4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8-1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8-1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4-2.6) and chronic GVHD (HR 1.7; 95% CI 1.2-2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5-0.9). CONCLUSIONS The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival.