-
1.
Allogeneic hematopoietic cell transplantation is equally effective in secondary acute lymphoblastic leukemia (ALL) compared to de-novo ALL-a report from the EBMT registry
Sadowska-Klasa, A., Zaucha, J. M., Labopin, M., Bourhis, J. H., Blaise, D., Yakoub-Agha, I., Salmenniemi, U., Passweg, J., Fegueux, N., Schroeder, T., et al
Bone marrow transplantation. 2024
-
-
-
Full text
-
Editor's Choice
Abstract
Secondary acute lymphoblastic leukemia (s-ALL) comprises up to 10% of ALL patients. However, data regarding s-ALL outcomes is limited. To answer what is the role of allogeneic hematopoietic cell transplantation (HCT) in s-ALL, a matched-pair analysis in a 1:2 ratio was conducted to compare outcomes between s-ALL and de novo ALL (dn-ALL) patients reported between 2000-2021 to the European Society for Blood and Marrow Transplantation registry. Among 9720 ALL patients, 351 (3.6%) were s-ALL, of which 80 were in first complete remission (CR1) with a known precedent primary diagnosis 58.8% solid tumor (ST), 41.2% hematological diseases (HD). The estimated 2-year relapse incidence (RI) was 19.1% (95%CI: 11-28.9), leukemia-free survival (LFS) 52.1% (95%CI: 39.6-63.2), non-relapse mortality (NRM) 28.8% (95%CI: 18.4-40), GvHD-free, relapse-free survival (GRFS) 39.4% (95%CI: 27.8-50.7), and overall survival (OS) 60.8% (95%CI: 47.9-71.4), and did not differ between ST and HD patients. In a matched-pair analysis, there was no difference in RI, GRFS, NRM, LFS, or OS between s-ALL and dn-ALL except for a higher incidence of chronic GvHD (51.9% vs. 31.4%) in s-ALL. To conclude, patients with s-ALL who received HCT in CR1 have comparable outcomes to patients with dn-ALL.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia, reported to the EBMT registry (n=9720)
Intervention
A detailed analysis cohort who were transplanted for secondary acute lymphoblastic leukaemia (s-ALL, n=80)
Comparison
Matched controls who were transplanted for de novo ALL (dn-ALL, n=80)
Outcome
The estimated 2-year relapse incidence (RI) was 19.1% (95%CI: 11-28.9), leukemia-free survival (LFS) 52.1% (95%CI: 39.6-63.2), non-relapse mortality (NRM) 28.8% (95%CI: 18.4-40), GvHD-free, relapse-free survival (GRFS) 39.4% (95%CI: 27.8-50.7), and overall survival (OS) 60.8% (95%CI: 47.9-71.4), and did not differ between solid tumour and haematological disease patients. In a matched-pair analysis, there was no difference in RI, GRFS, NRM, LFS, or OS between s-ALL and dn-ALL except for a higher incidence of chronic GvHD (51.9% vs. 31.4%) in s-ALL.
-
2.
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.
-
3.
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.
-
4.
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.
-
5.
Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Abou Dalle, I., Labopin, M., Kröger, N., Schroeder, T., Finke, J., Stelljes, M., Neubauer, A., Blaise, D., Yakoub-Agha, I., Salmenniemi, U., et al
Bone marrow transplantation. 2023
Abstract
Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47-2.24) p < 0.001 and HR = 1.54 (95% CI: 1.34-1.77), p < 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p < 0.001 and HR = 1.71 (95% CI: 1.51-1.94), p < 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease.
-
6.
Significance of HLA-E and its two NKG2 receptors in development of complications after allogeneic transplantation of hematopoietic stem cells
Siemaszko, J., Łacina, P., Szymczak, D., Szeremet, A., Majcherek, M., Czyż, A., Sobczyk-Kruszelnicka, M., Fidyk, W., Solarska, I., Nasiłowska-Adamska, B., et al
Frontiers in immunology. 2023;14:1227897
Abstract
Transplantation of hematopoietic stem cells (HSCT) is a procedure commonly used in treatment of various haematological disorders which is associated with significantly improved survival rates. However, one of its drawbacks is the possibility of development of post-transplant complications, including acute and chronic graft-versus-host disease (GvHD) or CMV infection. Various studies suggested that NK cells and their receptors may affect the transplant outcome. In the present study, patients and donors were found to significantly differ in the distribution of the NKG2A rs7301582 genetic variants - recipients carried the C allele more often than their donors (0.975 vs 0.865, p<0.0001). Increased soluble HLA-E (sHLA-E) levels detected in recipients' serum 30 days after transplantation seemed to play a prognostic and protective role. It was observed that recipients with higher sHLA-E levels were less prone to chronic GvHD (11.65 vs 6.33 pg/mL, p=0.033) or more severe acute GvHD grades II-IV (11.07 vs 8.04 pg/mL, p=0.081). Our results also showed an unfavourable role of HLA-E donor-recipient genetic incompatibility in CMV infection development after transplantation (OR=5.92, p=0.014). Frequencies of NK cells (both CD56dim and CD56bright) expressing NKG2C were elevated in recipients who developed CMV, especially 30 and 90 days post-transplantation (p<0.03). Percentages of NKG2C+ NK cells lacking NKG2A expression were also increased in these patients. Moreover, recipients carrying a NKG2C deletion characterized with decreased frequency of NKG2C+ NK cells (p<0.05). Our study confirms the importance of NK cells in the development of post-transplant complications and highlights the effect of HLA-E and NKG2C genetic variants, sHLA-E serum concentration, as well as NKG2C surface expression on transplant outcome.
-
7.
Impact of Cytogenetic Risk on Outcomes of Non-T Cell Depleted Haploidentical Hematopoietic Cell Transplantation in Patients with Relapsed or Refractory Acute Myeloid Leukemia
Nagler, A., Labopin, M., Dholaria, B., Ciceri, F., Fraccaroli, A., Blaise, D., Fanin, R., Bruno, B., Forcade, E., Vydra, J., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Baseline cytogenetics and disease status are key factors predicting the outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML). The importance of cytogenetic risk in patients with primary refractory or relapsed (R/R) AML undergoing haploidentical (Haplo) HCT is unknown. We studied the impact of cytogenetic risk in patients with R/R de novo AML with active disease who underwent non-T cell depleted Haplo-HCT with post-transplant cyclophosphamide from 2010-2020. OBJECTIVES Four hundred and forty patients with active disease at transplantation from EBMT database were analyzed [291 (66.1%) with intermediate-risk (AMLint) and 149 (44.1%) with adverse-risk cytogenetics (AMLadv)]. Impact of baseline cytogenetic risk on various transplant outcomes was evaluated. RESULTS Pre-transplant disease status was relapse in 48.1% and 26.8% and primary refractory in 51.9% and 73.2% of the patients with AMLint and AMLadv, respectively (p<0.0001). Two-year leukemia-free survival (LFS, 35.5% vs. 15.5%, p=0.001) and overall survival (OS, 39.2% vs. 20.1%, p=0.001) were better in AMLint versus AMLadv. In multivariate analysis, the relapse rate was significantly higher [hazard ratio (HR)=2.17 (95% CI 1.57-3.0)] and LFS [HR=1.71 (95% CI 1.31-2.22)] and OS [HR=1.69 (95% CI 1.29-2.22)], significantly lower for patients with AMLadv compared to AMLint, conditioning intensity did not affect leukemia relapse rate. Non-relapse mortality [HR=1.1 (95% CI: 0.7-1.74)] and GVHD-free, relapse-free survival [GRFS, HR=1.37 (95% CI: 1.06-1.77)] did not differ significantly between the risk groups. Disease status before transplant (primary refractory versus relapsed) or conditioning intensity did not impact main transplant outcomes. CONCLUSION Baseline cytogenetic risk remains a key prognostic factor for patients with R/R AML with persistent disease before non-T cell depleted Haplo-HCT.
-
8.
Longitudinal outcome over two decades of unrelated allogeneic stem cell transplantation for relapsed/refractory acute myeloid leukemia: an ALWP/EBMT analysis
Nagler, A., Ngoya, M., Galimard, J. E., Labopin, M., Bornhäuser, M., Stelljes, M., Finke, J., Ganser, A., Einsele, H., Kröger, N., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022
-
-
-
Full text
-
Editor's Choice
Abstract
INTRODUCTION We evaluated outcome of unrelated transplantation for primary refractory/relapsed (ref/rel) acute myeloid leukemia (AML) comparing two cohorts according to the year of transplant, 2000-2009 and 2010-2019. METHODS Multivariable analyses were performed using the Cox proportional-hazards regression model. RESULTS 3430 patients were included, 876 underwent a transplant between 2000-2009 and 2554 in 2010-2019. Median follow up was 8.7 (95% CI: 7.8-9.4) and 3.4 (95% CI: 3.1-3.6) years (p<0.001). Median age was 52 (18-77) and 56 (18-79) years (p<0.0001). 45.5% and 55.5% had refractory AML while 54.5% and 44.5 % had relapsed AML. Conditioning was myeloablative in 60% and 52%, respectively. Neutrophil recovery, day 100 incidence of acute and 2-year incidence of chronic graft-versus-host disease (GVHD) were similar between the two periods. Two-year relapse incidence was higher for patients transplanted in the 2000-2009 period vs. those transplanted in 2010-2019; 50.2% vs. 45.1%; (hazard ratio (HR)=0.85 (95% CI: 0.74-0.97), p=0. 002). Leukemia-free survival, overall survival and GVHD-free, relapse-free survival were lower for the 2000-2009 period, 26% vs. 32.1% (HR=0.87 (95% CI: 0.78-0.97), p=0.01), 32.1% vs. 38.1% (HR=0.86 (95% CI: 0.77-0.96), p=0.01) and 21.5% vs. 25.3% (HR=0.89 (95% CI: 0.81-0.99), p=0.03, respectively. Two-year non-relapse mortality was not significantly different, 23.8% vs. 23.7% (HR=0.91 (95% CI: 0.76-1.11), p=0.34. CONCLUSION Outcome of unrelated transplantation for patients with ref/rel AML has improved in the last two decades, rescuing about one third of the patients.
PICO Summary
Population
Adults transplanted for refractory/relapsed acute myeloid leukaemia (AML) and reported to the EBMT registry (n=3430)
Intervention
Transplantation between the years 2000-2009 (n=876)
Comparison
Transplantation between the years 2010-2019 (n=2554
Outcome
Median follow up was 8.7 (95% CI: 7.8-9.4) and 3.4 (95% CI: 3.1-3.6) years (2000-2009 and 2010-2019 respectively). Median age was 52 (18-77) and 56 (18-79) years. 45.5% and 55.5% had refractory AML while 54.5% and 44.5 % had relapsed AML. Conditioning was myeloablative in 60% and 52%, respectively. Neutrophil recovery, day 100 incidence of acute and 2-year incidence of chronic graft-versus-host disease (GVHD) were similar between the two periods. Two-year relapse incidence was higher for patients transplanted in the 2000-2009 period vs. those transplanted in 2010-2019; 50.2% vs. 45.1%; (hazard ratio (HR)=0.85 (95% CI: 0.74-0.97)). Leukemia-free survival, overall survival and GVHD-free, relapse-free survival were lower for the 2000-2009 period, 26% vs. 32.1% (HR=0.87 (95% CI: 0.78-0.97), 32.1% vs. 38.1% (HR=0.86 (95% CI: 0.77-0.96)) and 21.5% vs. 25.3% (HR=0.89 (95% CI: 0.81-0.99), respectively. Two-year non-relapse mortality was not significantly different, 23.8% vs. 23.7% (HR=0.91 (95% CI: 0.76-1.11).
-
9.
CNS Involvement at Initial Diagnosis and Risk of Relapse After Allogeneic HCT for Acute Lymphoblastic Leukemia in First Complete Remission
Kharfan-Dabaja, M. A., Labopin, M., Bazarbachi, A., Salmenniemi, U., Mielke, S., Chevallier, P., Thérèse Rubio, M., Balsat, M., Pioltelli, P., Menard, A. L., et al
HemaSphere. 2022;6(11):e788
Abstract
Outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult acute lymphoblastic leukemia (ALL) have improved over time. Studies have shown that total body irradiation (TBI) is the preferable type of myeloablative conditioning (MAC). However, outcomes based on central nervous system (CNS) involvement, namely CNS-positive versus CNS-negative, have not been compared. Here, we evaluated outcomes of 547 patients (CNS-positive = 96, CNS-negative = 451) who were allografted in the first complete remission (CR1) between 2009 and 2019. Primary endpoint was leukemia-free survival (LFS). Median follow-up was not different between the CNS-positive and CNS-negative groups (79 versus 67.2 months, P = 0.58). The CNS-positive group were younger (median age 31.3 versus 39.7 years, P = 0.004) and were allografted more recently (median year 2012 versus 2010, P = 0.003). In both groups, MAC was the preferred approach (82.3% versus 85.6%, P = 0.41). On multivariate analysis, the CNS-positive group had higher incidence of relapse (RI) (hazard ratio [HR] = 1.58 [95% confidence interval (CI) = 1.06-2.35], P = 0.025), but no adverse effect on LFS (HR = 1.38 [95% CI = 0.99-1.92], P = 0.057) or overall survival (OS) (HR = 1.28 [95% CI = 0.89-1.85], P = 0.18). A subgroup multivariate analysis limited to CNS-positive patients showed that a TBI-based MAC regimen resulted in better LFS (HR = 0.43 [95% CI = 0.22-0.83], P = 0.01) and OS (HR = 0.44 [95% CI = 0.21-0.92], P = 0.03) and lower RI (HR = 0.35 [95% CI = 0.15-0.79], P = 0.01). Another subgroup analysis in CNS-negative patients showed that MAC-TBI preparative regimens also showed a lower RI without a benefit in LFS or OS. While a MAC-TBI allo-HCT regimen may not be suitable to all, particularly for older patients with comorbidities, this approach should be considered for patients who are deemed fit and able to tolerate.
-
10.
20-Year Steady Increase in Survival of Adult Patients with Relapsed Philadelphia-Positive Acute Lymphoblastic Leukemia Post Allogeneic Hematopoietic Cell Transplantation
Bazarbachi, A., Labopin, M., Aljurf, M., Niittyvuopio, R., Balsat, M., Blaise, D., Yakoub-Agha, I., Grassi, A., Reinhardt, H. C., Lenhoff, S., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022
Abstract
PURPOSE Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains the first cause of transplant failure in patients with Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL). In other hematologic malignancies, therapeutic advances resulted in significant improvement over time in survival of patients relapsing after transplant. PATIENTS AND METHODS We compared outcomes at European Society for Blood and Marrow Transplantation (EBMT) participating centers of 899 adult patients with Ph(+) ALL who relapsed between 2000 and 2019 after allo-HCT performed in first complete remission. Median follow-up for alive patients was 56 months. RESULTS Overall, 116 patients relapsed between 2000 and 2004, 225 between 2005 and 2009, 294 between 2010 and 2014, and 264 between 2015 and 2019. Patient and transplant characteristics were similar over the four time periods except for a progressive increase in unrelated donors, peripheral blood stem cells, reduced intensity conditioning, and in vivo T-cell depletion and a progressive decrease in total body irradiation. The 2-year overall survival (OS) after relapse increased from 27.8% for patients relapsing between 2000 and 2004 to 54.8% for 2015 and 2019 (P = 0.001). A second allo-HCT within 2 years after relapse was performed in 13.9% of patients resulting in a 2-year OS of 35.9%. In multivariate analysis, OS from relapse was positively affected by a longer time from transplant to relapse and the year of relapse. CONCLUSIONS We observed a major progressive improvement in OS from posttransplant relapse for patients with Ph(+) ALL over the years, likely multifactorial including transplant-related factors, posttransplant salvage, and improvement in supportive care. These large-scale real-world data can serve as a benchmark for future studies in this setting.