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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
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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.
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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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Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia: A Study of the Acute Leukemia Working Party of the EBMT
Spyridonidis, A., Labopin, M., Savani, B., Giebel, S., Bug, G., Schönland, S., Kröger, N., Stelljes, M., Schroeder, T., McDonald, A., et al
HemaSphere. 2023;7(1):e812
Abstract
In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P <0.0001). In a multivariate model adjusted for age, type of ALL, and other prognostic factors, leukemia-free survival (primary endpoint) as well as relapse, nonrelapse mortality, overall survival, and GVHD-free, relapse-free survival were not influenced by the TBI dose. These results were confirmed when we focused on patients <55 years of age (median 47 years). Patients with Ph-positive ALL or T-ALL had significantly better survival outcomes than ones with Ph-negative B-ALL, mainly due to significantly fewer relapses. We conclude that 8-Gray TBI is sufficient for adult patients with ALL transplanted in CR-1 with no additional benefit of augmenting the conditioning intensity to 12-Gray.
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Total body irradiation versus busulfan based intermediate intensity conditioning for stem cell transplantation in ALL patients >45 years-a registry-based study by the Acute Leukemia Working Party of the EBMT
Hirschbühl, K., Labopin, M., Polge, E., Blaise, D., Bourhis, J. H., Socié, G., Forcade, E., Yakoub-Agha, I., Labussière-Wallet, H., Bethge, W., et al
Bone marrow transplantation. 2023
Abstract
Allogeneic hematopoietic cell transplantation is a potentially curative treatment in high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens based on ≥12 Gray total body irradiation (TBI) represent the current standard in patients ≤45 years, whereas elderly patients frequently receive intermediate intensity conditioning (IIC) to reduce toxicity. To evaluate the role of TBI as a backbone of IIC in ALL, a retrospective, registry-based study included patients >45 years transplanted from matched donors in first complete remission, who had received either fludarabine/TBI 8 Gy (FluTBI8, n = 262), or the most popular, irradiation-free alternative fludarabine/busulfan, comprising busulfan 6.4 mg/kg (FluBu6.4, n = 188) or 9.6 mg/kg (FluBu9.6, n = 51). At two years, overall survival (OS) was 68.5%, 57%, and 62.2%, leukemia-free survival (LFS) was 58%, 42.7%, and 45%, relapse incidence (RI) was 27.2%, 40%, and 30.9%, and non-relapse-mortality (NRM) was 23.1%, 20.7%, and 26.8% for patients receiving FluTBI8Gy, FluBu6.4, and FluBu9.6, respectively. In multivariate analysis, the risk of NRM, acute and chronic graft-versus-host disease was not influenced by conditioning. However, RI was higher after FluBu6.4 (hazard ratio [HR] [95% CI]: 1.85 [1.16-2.95]), and LFS was lower after both FluBu6.4 (HR: 1.56 [1.09-2.23]) and FluBu9.6 (HR: 1.63 [1.02-2.58]) as compared to FluTBI8. Although only resulting in a non-significant advantage in OS, this observation indicates a stronger anti-leukemic efficacy of TBI-based intermediate intensity conditioning.
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Autologous versus allogeneic hematopoietic cell transplantation for older patients with acute lymphoblastic leukemia. An analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Giebel, S., Labopin, M., Houhou, M., Caillot, D., Finke, J., Blaise, D., Fegueux, N., Ethell, M., Cornelissen, J. J., Forcade, E., et al
Bone marrow transplantation. 2023;58(4):393-400
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced intensity conditioning (RIC) is an option for elderly patients with acute lymphoblastic leukemia (ALL). We retrospectively compared results of RIC-allo-HCT from either a matched sibling donor (MSD, n = 209) or matched unrelated donor (MUD, n = 209) with autologous (auto, n = 142) HCT for patients aged 55 years or more treated in first complete remission (CR1) between 2000 and 2018. The probabilities of leukemia-free survival (LFS) at 5 years were 34% for RIC-allo-HCT versus 39% for auto-HCT (p = 0.11) while overall survival (OS) rates were 42% versus 45% (p = 0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 41% versus 51% (p = 0.22) and 25% versus 10% (p = 0.001), respectively. In a multivariate model, using auto-HCT as reference, the risk of NRM was increased for MSD-HCT (Hazard ratio [HR] = 2.1, p = 0.02) and MUD-HCT (HR = 3.08, p < 0.001), which for MUD-HCT translated into a decreased chance of LFS (HR = 1.55, p = 0.01) and OS (HR = 1.62, p = 0.008). No significant associations were found with respect to the risk of relapse. We conclude that for patients with ALL in CR1, aged above 55 years, auto-HCT may be considered a transplant option alternative to RIC-allo-HCT, although its value requires verification in prospective trials.
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Fludarabine or cyclophosphamide in combination with total body irradiation as myeloablative conditioning prior to allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia: an analysis by the Acute Leukemia Working Party of the EBMT
Giebel, S., Labopin, M., Socié, G., Aljurf, M., Salmenniemi, U., Labussière-Wallet, H., Srour, M., Kröger, N., Zahrani, M. A., Lioure, B., et al
Bone marrow transplantation. 2023
Abstract
In this registry-based study we retrospectively compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with acute lymphoblastic leukemia (ALL) following conditioning with total body irradiation (TBI) combined with either cyclophosphamide (Cy) or fludarabine (Flu). TBI 12 Gy + Cy was used in 2105 cases while TBI 12 Gy + Flu was administered to 150 patients in first or second complete remission. In a multivariate model adjusted for other prognostic factors, TBI/Cy conditioning was associated with a reduced risk of relapse (HR = 0.69, p = 0.049) and increased risk of grade 2-4 acute graft-versus-host disease (GVHD, HR = 1.57, p = 0.03) without significant effect on other transplantation outcomes. In a matched-pair analysis the use of TBI/Cy as compared to TBI/Flu was associated with a significantly reduced rate of relapse (18% vs. 30% at 2 years, p = 0.015) without significant effect on non-relapse mortality, GVHD and survival. We conclude that the use of myeloablative TBI/Cy as conditioning prior to allo-HCT for adult patients with ALL in complete remission is associated with lower risk of relapse rate compared to TBI/Flu and therefore should probably be considered a preferable regimen.
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Comparative study of treosulfan plus Fludarabine (FT14) with busulfan plus Fludarabine (FB4) for acute myeloid leukemia in first or second complete remission: An analysis from the European Society for Blood and Marrow Transplantation (EBMT) Acute Leukemia Working Party (ALWP)
Gavriilaki, E., Labopin, M., Sakellari, I., Salmenniemi, U., Yakoub-Agha, I., Potter, V., Berceanu, A., Rambaldi, A., Hilgendorf, I., Kröger, N., et al
Bone marrow transplantation. 2022
Abstract
Different doses of treosulfan plus fludarabine have shown advantage over reduced intensity regimens. However, data comparing higher doses of treosulfan to myeloablative busulfan are limited. Thus, we compared outcomes between FT14 (fludarabine 150/160 mg/m(2) and treosulfan 42 g/m(2), or FT14) over FB4 (fludarabine 150/160 mg/m(2) and busulfan 12.8 mg/kg). We retrospectively studied patients from European Society for Blood and Marrow Transplantation registry: a) adults diagnosed with acute myeloid leukemia (AML), b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated or sibling donor (2010-2020), c) HSCT at first or second complete remission, d) conditioning with FT14 or FB4. FT14 recipients (n = 678) were older, with higher rates of secondary AML, unrelated donors, peripheral blood grafts, and adverse cytogenetics, but lower percentage of female donor to male recipient compared to FB4 (n = 2025). Analysis was stratified on age. In patients aged < 55 years, FT14 was associated with higher relapse incidence (RI) and lower Leukemia-Free Survival (LFS). In patients aged≥55 years, acute GVHD CI was higher in FB4, without significant differences in other outcomes. Although FT14 has been used for higher-risk HSCT patients, our large real-world multicenter study suggests that FB4 is associated with better outcomes compared to FT14 in younger patients.
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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.
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Haploidentical Versus Matched Sibling Donor Hematopoietic Stem Cell Transplantation for Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia: A Study From the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Nagler, A., Labopin, M., Swoboda, R., Pioltelli, P., Arat, M., Yakoub-Agha, I., Kulagin, A., Maria Raiola, A., Ozdogu, H., Risitano, A., et al
HemaSphere. 2022;6(11):e790
Abstract
The results of haploidentical stem cell transplantation (haploHCT) for patients with acute lymphoblastic leukemia (ALL) transplanted in active disease remain largely unknown. We retrospectively analyzed adult patients with R/R ALL who underwent haploHCT or matched sibling donor (MSD-HCT) as a first transplantation between 2012 and 2020. The analysis comprised 274 patients, 94 had a haploHCT, and 180 had an MSD-HCT. The median follow-up was 32 months. The median age was 33 (range 18-76) and 37 (18-76) years in the haplo- and MSD-HCT groups, respectively. Post-transplant cyclophosphamide (PTCy) was used in 88% of haploHCT and in 4% of the MSD-HCT group. Graft-versus-host disease grade III-IV was higher in haploHCT than in the MSD-HCT group (18% versus 9%; P = 0.042). The 2-year chronic (c) graft-versus-host disease rates were 17% versus 33% (hazard ratio [HR] = 0.56; P = 0.14), respectively. By multivariate analysis, relapse incidence, and leukemia-free survival were not significatively different between the transplant groups, while nonrelapse mortality (NRM) was significantly higher (25% versus 18% at 2 years; HR = 2.03; P = 0.042) and overall survival (OS) lower (22% versus 38% at 2 years; HR = 1.72; P = 0.009) in the haploHCT group compared with the MSD-HCT group. We conclude that the 2-year OS of R/R ALL patients undergoing MSD transplants is significantly better than in haploHCT with a higher NRM in the latter.
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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
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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).