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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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3.
Fludarabine versus cyclophospamide in combination with myeloablative total body irradiation as conditioning for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Giebel, S., Labopin, M., Schroeder, T., Swoboda, R., Maertens, J., Bourhis, J. H., Grillo, G., Salmenniemi, U., Hilgendorf, I., Kröger, N., et al
American journal of hematology. 2023
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Editor's Choice
Abstract
Total body irradiation (TBI) at a dose of 12 Gy combined with cyclophosphamide (CyTBI12Gy) is one of the standard myeloablative regimens for patients with acute myeloid leukemia (AML) treated with allogeneic hematopoietic cell transplantation (allo-HCT). In clinical practice, cyclophosphamide may be substituted with fludarabine (FluTBI12Gy) to reduce toxicity. We retrospectively compared outcomes of CyTBI12Gy with FluTBI12Gy for patients with AML treated in complete remission (CR) with allo-HCT from either a matched sibling or unrelated donor. Of 1684 adults who met inclusion criteria, 109 patients in each group were included in a matched-pair analysis. The cumulative incidence of relapse at 2 years was 25% in the FluTBI12Gy compared to 28% in the CyTBI12Gy group (p = .44) while non-relapse mortality (NRM) was 17% versus 19%, (p = .89) respectively. The rates of leukemia-free survival and overall survival were 65% versus 54% (p = .28) and 70% versus 60.5% (p = .17). Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly lower for FluTBI12Gy than CyTBI12Gy (16% vs. 34%, p = .005), while the incidences of grade 3-4 acute GVHD and chronic GVHD did not differ significantly. The probability of GVHD and relapse-free survival was 49% in the FluTBI12Gy and 41% in the CyTBI12Gy group (p = .17). We conclude that for patients with AML treated with allo-HCT in CR, cyclophosphamide may be substituted with fludarabine in a regimen based on TBI at a dose of 12 Gy without negative impact on the efficacy. FluTBI12Gy is associated with reduced risk of grade 2-4 acute GVHD and encouraging survival rates.
PICO Summary
Population
Matched pairs identified from the EBMT registry: adults with AML treated in complete remission treated with allo-HCT from either a matched sibling or unrelated donor (n=218)
Intervention
Total body irradiation at a dose of 12 Gy combined with cyclophosphamide (CyTBI12Gy, n=109)
Comparison
Total body irradiation at a dose of 12 Gy combined with fludarabine (FluTBI12Gy, n=109)
Outcome
The cumulative incidence of relapse at 2 years was 25% in the FluTBI12Gy compared to 28% in the CyTBI12Gy group while non-relapse mortality (NRM) was 17% versus 19%, respectively. The rates of leukemia-free survival and overall survival were 65% versus 54% and 70% versus 60.5%. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was significantly lower for FluTBI12Gy than CyTBI12Gy (16% vs. 34%), while the incidences of grade 3-4 acute GVHD and chronic GVHD did not differ significantly. The probability of GVHD and relapse-free survival was 49% in the FluTBI12Gy and 41% in the CyTBI12Gy group.
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4.
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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Total body irradiation plus fludarabine versus thiotepa, busulfan plus fludarabine as a myeloablative conditioning for adults with acute lymphoblastic leukemia treated with haploidentical hematopoietic cell transplantation. A study by the Acute Leukemia Working Party of the EBMT
Swoboda, R., Labopin, M., Giebel, S., Angelucci, E., Arat, M., Aljurf, M., Sica, S., Pavlu, J., Socié, G., Bernasconi, P., et al
Bone marrow transplantation. 2022
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Full text
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Editor's Choice
Abstract
Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.
PICO Summary
Population
Adults with acute lymphoblastic leukemia (ALL) treated with haploidentical (n=haematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide (n=236)
Intervention
Fludarabine + total body irradiation conditioning (Flu-TBI, n=117)
Comparison
Thiotepa + iv. busulfan + fludarabine conditioning (TBF, n=119)
Outcome
In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%). There was a tendency towards reduced incidence of relapse after TBF. Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34) but an increased risk of relapse (HR = 2.59) without significant effect on survival and graft-versus-host disease.
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Total body irradiation plus fludarabine versus busulfan plus fludarabine as a myeloablative conditioning for adults with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation. A study on behalf of the Acute Leukemia Working Party of the EBMT
Swoboda, R., Labopin, M., Giebel, S., Schroeder, T., Kröger, N., Arat, M., Savani, B., Spyridonidis, A., Hamladji, R. M., Potter, V., et al
Bone marrow transplantation. 2022
Abstract
Cyclophosphamide is frequently substituted with fludarabine (Flu) in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to compare retrospectively, total body irradiation (12 Gy) plus Flu (FluTBI12) versus busulfan (Bu) plus Flu (FB4) as a myeloablative conditioning before allo-HCT in patients with acute myeloid leukemia (AML). Out of 3203 patients who met the inclusion criteria, 109 patients treated with FluTBI12 and 213 treated with FB4 were included in a final matched-pair analysis. In both groups, median patient age was 41 years, first or second complete remission (CR1/CR2) proportion was 78%/22%, allo-HCT from an unrelated donor was performed in 78% of patients. The probabilities of leukemia-free survival and overall survival at 2 years in FluTBI12 and FB4 groups were 65% vs. 60% (p = 0.64) and 70% vs. 72% (p = 0.87), respectively. The cumulative incidence of relapse was 19% vs. 29% (p = 0.11), while non-relapse mortality was 16% vs. 11%, respectively (p = 0.13). There were no statistical differences in both acute and chronic graft-versus-host disease (GVHD) incidence. The probability of GVHD-free, relapse-free survival (GRFS) was 49% for both groups. FluTBI12 and FB4 are comparable myeloablative regimens before allo-HCT in AML patients transplanted in CR1 and CR2.
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Tandem autologous hematopoietic cell transplantation with sequential use of total marrow irradiation and high-dose melphalan in multiple myeloma
Giebel, S., Sobczyk-Kruszelnicka, M., Blamek, S., Saduś-Wojciechowska, M., Najda, J., Czerw, T., Mendrek, W., Woźniak, G., Jochymek, B., Radwan, M., et al
Bone marrow transplantation. 2021;56(6):1297-1304
Abstract
The goal of this phase II trial was to evaluate safety and efficacy of a tandem autologous hematopoietic cell transplantation (auto-HCT) using sequentially total marrow irradiation (TMI) at the dose of 12 Gy (4 Gy on days -3, -2, and -1) and melphalan 200 mg/m(2) for patients with multiple myeloma (MM). TMI was performed using helical tomotherapy. Additional "boosts" (total 24 Gy) were applied for patients with active lesions as revealed by PET-FDG. Fifty patients with median age 58 years (41-64 years) were included and received tandem auto-HCT. TMI resulted in absolute neutropenia in all patients. Grade 3 infections were reported in 30% patients. Other toxicities were rare. Proportion of patients who achieved at least very good partial response increased from 46% before the first auto-HCT to 82% after tandem transplantation. Complete remission rates changed from 10% to 42%, respectively. The probabilities of overall and progression-free survival at 5 years were 74% and 55%, respectively. No patient died without progression. We conclude that conditioning with TMI ± PET-guided "boosts" represents personalized treatment approach in MM and is characterized by very good toxicity profile. Tandem auto-HCT using TMI in sequence with high-dose melphalan appears safe with encouraging early efficacy.
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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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Single Dose Daily Fractionated Is Not Inferior To Twice A Day Fractionated Total Body Irradiation Prior To Allogeneic Stem Cell Transplantation For Acute Leukemia: A Useful Practice Simplification Resulting From The Sarasin Study
Belkacemi, Y., Labopin, M., Giebel, S., Gorin, N. C., Loganadane, G., Miszczyk, L., Michallet, M., Socie, G., Schaap, N. P., Cornelissen, J. J., et al
International journal of radiation oncology, biology, physics. 2018
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Full text
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Editor's Choice
Abstract
PURPOSE Total-body irradiation (TBI) is a major constituent of myeloablative conditioning regimens. The standard technique consists of 12Gy in 6 fractions over 3 days. The SARASIN study aimed to compare standard-fractionation to one-daily fractionation prior to transplant in leukemia. MATERIAL AND METHODS We retrospectively compared TBI regimens delivered in 2993 patients from the EBMT database, transplanted between 2000 and 2014 for acute lymphoblastic (ALL, n=1729) or acute myelogenous (AML, n=1264) leukemia. TBI was delivered as either 12Gy in 6 fractions (group 1: considered as the reference group; ALL, n=1362 and AML, n=857), or 9-12Gy in 2 fractions (group 2; ALL, n=173 and AML, n=256), or 12Gy in 3-4 fractions (group 3; ALL, n=194 and AML, n=151). RESULTS The median follow-up was 60 and 84 months in ALL and AML patients, respectively. At 5-years, leukemia-free survival, overall survival, relapse incidence and non-relapse mortality were 46.6%, 50.4%, 28.8%, 24.6% in ALL and 46.6%, 48.9%, 29.7% and 23.6% in AML, respectively. In multivariate analyses, outcomes of groups 2 and 3 were not statistically different from group 1. Cumulative incidence of secondary malignancies (SMs) was significantly higher in group 2 (7.2%) (group 2 versus 1, p<10(-6)). However, group 2 was not associated with an increase in SMs when considering non-T depletion transplanted patients. CONCLUSION We showed that 12Gy-FTBI dose delivered either in 2 or in one fraction per day over 3-4 days resulted in non-significant difference disease control and survival. However, one-day fractionation may be associated with a higher risk of mucositis and hemorrhagic cystitis. The absence of significant difference in SMs incidence in the non-T-cell depleted group should be interpreted with caution in the context of a retrospective study design. Our findings are important to consider for radiotherapy departments organization. In depth analyses of other non-lethal toxicities and late effects are required.
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Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission: An analysis by the Acute Leukemia Working Party of the EBMT
Giebel, S., Labopin, M., Potter, M., Poire, X., Sengeloev, H., Socie, G., Huynh, A., Afanasyev, B. V., Schanz, U., Ringden, O., et al
European journal of cancer (Oxford, England : 1990). 2018;96:73-81
Abstract
BACKGROUND Allogeneic haematopoietic stem cell transplantation (alloHSCT) is considered a standard treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) achieving complete remission after induction containing tyrosine kinase inhibitors (TKIs). METHODS We retrospectively compared results of myeloablative alloHSCT from either matched sibling donor (MSD) or unrelated donor (URD) with autologous (auto) HSCT for adults with Ph+ ALL in molecular remission, treated between 2007 and 2014. RESULTS In univariate analysis, the incidence of relapse at 2 years was 47% after autoHSCT, 28% after MSD-HSCT and 19% after URD-HSCT (P = 0.0002). Respective rates of non-relapse mortality were 2%, 18%, and 22% (P = 0.001). The probabilities of leukaemia-free survival were 52%, 55% and 60% (P = 0.69), while overall survival rates were 70%, 70% and 69% (P = 0.58), respectively. In multivariate analysis, there was a trend towards increased risk of overall mortality after MSD-HSCT (hazard ratio [HR], 1.5, P = 0.12) and URD-HSCT (HR, 1.6, P = 0.08) when referred to autoHSCT. The use of total body irradiation (TBI)-based regimens was associated with reduced risk of relapse (HR, 0.65, P = 0.02) and overall mortality (HR, 0.67, P = 0.01). CONCLUSION In the era of TKIs, outcomes of myeloablative autoHSCT and alloHSCT for patients with Ph+ ALL in first molecular remission are comparable. Therefore, autoHSCT appears to be an attractive treatment option potentially allowing for circumvention of alloHSCT sequelae. Irrespective of the type of donor, TBI-based regimens should be considered the preferable type of conditioning for Ph+ ALL.