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1.
Complex karyotype but not other cytogenetic abnormalities is associated with worse posttransplant survival of patients with nucleophosmin 1-mutated acute myeloid leukemia: A study from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party
Moukalled, N., Labopin, M., Versluis, J., Socié, G., Blaise, D., Salmenniemi, U., Rambaldi, A., Gedde-Dahl, T., Tholouli, E., Kröger, N., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
In the 2022 European LeukemiaNet classification, patients with nucleophosmin 1 (NPM1)-mutated acute myeloid leukemia (AML) were classified in the adverse-risk category in the presence of high-risk cytogenetics (CG). Nonetheless, the impact of various CG aberrations on posttransplant outcomes remains to be unraveled. This registry study analyzed adult patients with NPM1-mutated de novo AML who underwent their first allogeneic hematopoietic cell transplantation in the first complete remission from 2005 to 2021. A total of 3275 patients were identified, 2782 had normal karyotype, 493 had chromosomal aberrations including 160 with adverse-risk CG, 72 patients had complex karyotype (CK), and 66 monosomal karyotype (MK). Overall, 2377 (73%) patients had FLT3-ITD. On univariate analysis, only FLT3-ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio [HR] 1.72, p = .009). In the subgroup of 493 patients with aberrant CG, the 2-year leukemia-free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p = .025; and 1.99, p = .003 respectively) and worse LFS (HR 1.62, p = .018; and 1.64, p = .011 respectively) while FLT3-ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91, p = .002). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1-mutated AML. Nevertheless, even for this subgroup, a significant proportion of patients can achieve long-term posttransplant survival.
PICO Summary
Population
Adults with NPM1-mutated de novo AML with known cytogenetic and FLT3-ITD status, reported to the EBMT registry (n=3275)
Intervention
Analysis of the impact of high-risk cytogenetics (CG) on allogeneic hematopoietic cell transplantation in the first complete remission.
Comparison
None
Outcome
Overall, 2377 (73%) patients had FLT3-ITD. On univariate analysis, only FLT3-ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio [HR] 1.72). In the subgroup of 493 patients with aberrant CG, the 2-year leukemia-free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p = .025; and 1.99) and worse LFS (HR 1.62, p = .018; and 1.64 respectively) while FLT3-ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1-mutated AML.
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2.
Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with hyperdiploid complex karyotype
Poiré, X., Labopin, M., Polge, E., Ganser, A., Socié, G., Gedde-Dahl, T., Forcade, E., Finke, J., Chalandon, Y., Bulabois, C. E., et al
Bone marrow transplantation. 2023
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the best consolidation strategy for acute myeloid leukemia (AML) with complex karyotype (CK). However, CK is a heterogenous and highly diverse entity. Numerical abnormalities have been associated with a controversial prognosis and AML with only multiple numerical abnormalities known as pure hyperdiploid karyotype (HDK) may have a distinct prognosis after allo-HCT compared to non-pure HDK CK AML. A total of 236 patients were identified within the EBMT registry as having HDK comprising 95 pure (pHDK) and 141 with other cytogenetic abnormalities (HDK+). The 2-year probability of leukemia-free survival (LFS) was 50% for pHDK and 31% for HDK+ (p = 0.003). The 2-year probability of overall survival (OS) was 57% for pHDK and 36% for HDK+ (p = 0.007). The 2-year cumulative incidence of relapse (RI) was 22% for pHDK and 44% for HDK+ (p = 0.001). The 2-year probability of graft-versus-host disease (GvHD)-free and relapse-free survival (GRFS) was 36% for pHDK and 21% for HDK+ (p = 0.01). On multivariate analysis, pHDK remained associated with significantly better LFS, OS and GRFS and lower RI (all p-values <0.004). pHDK AML constitutes probably a distinct cytogenetic entity from HDK+ or other non-hyperdiploid CK AML with better outcomes after allo-HCT.
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3.
Survival advantage of treosulfan plus fludarabine (FT14) compared to busulfan plus fludarabine (FB4) in active acute myeloid leukemia post allogeneic transplantation: an analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP)
Gavriilaki, E., Sakellari, I., Labopin, M., Bornhäuser, M., Hamladji, R. M., Casper, J., Edinger, M., Zák, P., Yakoub-Agha, I., Ciceri, F., et al
Bone marrow transplantation. 2023
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Full text
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Editor's Choice
Abstract
We compared FT14 (fludarabine 150-160 mg/m(2), treosulfan 42 g/m(2)) versus FB4 (fludarabine 150-160 mg/m(2), busulfan 12.8 mg/kg) in acute myeloid leukemia (AML) transplanted at primary refractory/relapsed disease. We retrospectively studied: (a) adults diagnosed with AML, (b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010-2020), (c) HSCT with primary refractory/relapsed disease, (d) conditioning regimen with FT14 or FB4. We studied 346 patients, 113 transplanted with FT14, and 233 with FΒ4. FT14 patients were significantly older, more frequently had an unrelated donor and had received a lower dose of fludarabine. Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV and extensive chronic GVHD was similar. With a median follow-up of 28.7 months, 2-year CI of relapse was 43.4% in FT14 versus 53.2% in FB4, while non-relapse mortality (NRM) was respectively 20.8% versus 22.6%. This led to 2-year leukemia-free survival (LFS) of 35.8% for FT14 versus 24.2% in FB4, and overall survival (OS) of 44.4% versus 34%. Adverse cytogenetics and conditioning regimen independently predicted CI of relapse. Furthermore, conditioning regimen was the only independent predictor of LFS, OS, and GVHD-free/relapse-free survival. Therefore, our real-world multicenter study suggests that FT14 is associated with better outcomes in primary refractory/relapsed AML.
PICO Summary
Population
Adults identified from the EBMT registry, meeting the following criteria: diagnosed with AML, recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010-2020), and with primary refractory/relapsed disease, (n=346)
Intervention
Fludarabine 150-160 mg/m(2), treosulfan 42 g/m(2) conditioning (FT14, n=113)
Comparison
Fludarabine 150-160 mg/m(2), busulfan 12.8 mg/kg) conditioning (FB4, n=233)
Outcome
FT14 patients were significantly older, more frequently had an unrelated donor and had received a lower dose of fludarabine. Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV and extensive chronic GVHD was similar. With a median follow-up of 28.7 months, 2-year CI of relapse was 43.4% in FT14 versus 53.2% in FB4, while non-relapse mortality (NRM) was respectively 20.8% versus 22.6%. This led to 2-year leukemia-free survival (LFS) of 35.8% for FT14 versus 24.2% in FB4, and overall survival (OS) of 44.4% versus 34%. Adverse cytogenetics and conditioning regimen independently predicted CI of relapse. Furthermore, conditioning regimen was the only independent predictor of LFS, OS, and GVHD-free/relapse-free survival.
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4.
Non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary versus de novo AML in first complete remission: a study from the ALWP/EBMT
Nagler, A., Labopin, M., Blaise, D., Raiola, A. M., Corral, L. L., Bramanti, S., Sica, S., Kwon, M., Koc, Y., Pavlu, J., et al
Journal of hematology & oncology. 2023;16(1):58
Abstract
We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p < 0.0001, had better transplantation comorbidity index (HCT-CI) ≥ 3 21.3% versus 40.8%, p < 0.0001 and Karnofsky performance status (KPS) with KPS ≥ 90 in 78% versus 68.5%, respectively, p = 0.002. The two patient groups did not differ with respect to gender, cytomegalovirus serostatus, and cell source. Median time from diagnosis to HaploSCT was 5.2 versus 4.9 months, respectively, p = 0.005. Fewer sAML patients received myeloablative conditioning 35.1% versus 50.1%, p < 0.0001. Two hundred and eleven sAML and 410 de novo AML patients were included in the matched-pair analysis matching two de novo AML with each sAML. No significant difference was observed in any transplantation outcome parameter between the sAML versus de novo AML groups. Two-year non-relapse mortality and relapse incidence did not differ with HaploSCT for de novo versus sAML; 21.4% versus 21%, hazard ratio (HR) = 0.98, p = 0.9 and 23.4% versus 20.6%, HR = 0.92, p = 0.67, respectively. Two-year leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)-free, relapse-free survival were also not different between the de novo AML and sAML groups 55.2% versus 58.4%, HR = 0.95, p = 0.67; 61.4% versus 66.4%, HR = 0.91, p = 0.51 and 46.3% versus 48.2%, HR = 0.92, p = 0.48, respectively. Similarly, the incidence of engraftment as well as acute and chronic GVHD was similar between the 2 cohorts. In conclusion, HaploSCT with PTCy may be able to overcome the bad prognosis of sAML as results are not significantly different to those of HaploSCT in de novo AML.
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5.
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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6.
The role of anti-thymocyte globulin in allogeneic stem cell transplantation (HSCT) from HLA-matched unrelated donors (MUD) for secondary AML in remission: a study from the ALWP /EBMT
Nagler, A., Labopin, M., Kröger, N., Schroeder, T., Gedde-Dahl, T., Eder, M., Franke, G. N., Blau, I. W., Salmenniemi, U., Socie, G., et al
Bone marrow transplantation. 2023
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Full text
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Editor's Choice
Abstract
We compared outcomes, of 1609 patients with secondary acute myeloid leukemia (sAML) undergoing allogeneic transplantation (HSCT) in first complete remission (CR1) from matched unrelated donors (MUD) from 2010 to 2021, receiving or not receiving anti-thymocyte globulin (ATG) (ATG-1308, no ATG-301). Median age was 60.9 (range, 18.5-77.8) and 61.1 (range, 21.8-75.7) years, (p = 0.3). Graft versus host disease (GVHD) prophylaxis was cyclosporin-A with methotrexate (41%) or mycophenolate mofetil (38.2%), without significant differences between groups. Day 28, engraftment (ANC > 0.5 × 10(9)/L) was 92.3% vs 95.3% (p = 0.17), respectively. On multivariate analysis, ATG was associated with lower incidence of grade II-IV and grade III-IV acute GVHD (p = 0.002 and p = 0.015), total and extensive chronic GVHD (p = 0.008 and p < 0.0001), and relapse incidence (RI) (p = 0.039), while non-relapse mortality (NRM) did not differ (p = 0.51). Overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were significantly higher in the ATG vs no ATG group, HR = 0.76 (95% CI 0.61-0.95, p = 0.014) and HR = 0.68 (95% CI 0.57-0.8, p < 0.0001), with a tendency for better leukemia-free survival (LFS), HR = 0.82 (95% CI 0.67-1, p = 0.051). The main causes of death were the original disease, infection, and GVHD. In conclusion, ATG reduces GVHD and improves LFS, OS, and GRFS in sAML patients without increasing the RI, despite sAML being a high-risk disease.
PICO Summary
Population
Adults with secondary acute myeloid leukemia (sAML) undergoing allogeneic HSCT) in first complete remission from matched unrelated donors and reported to the EBMT registry (n=1609)
Intervention
Anti-thymocyte globulin (ATG) included in GvHD prophylaxis (n=1308)
Comparison
No ATG included in GvHD prophylaxis (n=301)
Outcome
Day 28, engraftment (ANC > 0.5 × 10(9)/L) was 92.3% vs 95.3%, respectively. On multivariate analysis, ATG was associated with lower incidence of grade II-IV and grade III-IV acute GVHD, total and extensive chronic GVHD, and relapse incidence (RI), while non-relapse mortality (NRM) did not differ. Overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were significantly higher in the ATG vs no ATG group, HR = 0.76 (95% CI 0.61-0.95) and HR = 0.68 (95% CI 0.57-0.8), with a tendency for better leukemia-free survival (LFS), HR = 0.82 (95% CI 0.67-1). The main causes of death were the original disease, infection, and GVHD.
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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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Comparison of fludarabine/melphalan (FluMel) with fludarabine/melphalan/BCNU or thiotepa (FBM/FTM) in patients with AML in first complete remission undergoing allogeneic hematopoietic stem cell transplantation - a registry study on behalf of the EBMT Acute Leukemia Working Party
Duque-Afonso, J., Finke, J., Ngoya, M., Galimard, J. E., Craddock, C., Raj, K., Bloor, A., Nicholson, E., Eder, M., Kim, O., et al
Bone marrow transplantation. 2023
Abstract
Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m(2) (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m(2). We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.
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10.
Validation of the transplant conditioning intensity (TCI) index for allogeneic hematopoietic cell transplantation
Spyridonidis, A., Labopin, M., Gedde-Dahl, T., Ganser, A., Stelljes, M., Craddock, C., Wagner-Drouet, E. M., Versluis, J., Schroeder, T., Blau, I. W., et al
Bone marrow transplantation. 2023
Abstract
The intensity of the conditioning regimen given before allogeneic hematopoietic cell transplantation (allo-HCT) can vary substantially. To confirm the ability of the recently developed transplant conditioning intensity (TCI) score to stratify the preparative regimens of allo-HCT, we used an independent and contemporary patient cohort of 4060 transplant recipients with acute myeloid leukemia meeting inclusion criteria from the discovery study (allo-HCT in first complete remission, matched donor), but who were allografted in a more recent period (2018-2021) and were one decade older (55-75 years, median 63.4 years), we assigned them to a TCI category (low n = 1934, 48%; intermediate n = 1948, 48%, high n = 178, 4%) according to the calculated TCI score ([1-2], [2.5-3.5], [4-6], respectively), and examined the validity of the TCI category in predicting early non-relapse mortality (NRM), 2-year NRM and relapse (REL). In the unadjusted comparison, the TCI index provided a significant risk stratification for d100 and d180 NRM, NRM and REL risk. In the multivariate analysis adjusted for significant variables, there was an independent association of TCI with early NRM, NRM and REL. In summary, we confirm in contemporary treated patients that TCI reflects the conditioning regimen related morbidity and anti-leukemic efficacy satisfactorily and across other established prognostic factors.