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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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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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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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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 + 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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Comparison of reduced-intensity conditioning regimens in patients with acute lymphoblastic leukemia >45 years undergoing allogeneic stem cell transplantation-a retrospective study by the Acute Leukemia Working Party of EBMT
Peric, Z., Labopin, M., Peczynski, C., Polge, E., Cornelissen, J., Carpenter, B., Potter, M., Malladi, R., Byrne, J., Schouten, H., et al
Bone marrow transplantation. 2020
Abstract
The optimal reduced-intensity conditioning (RIC) for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively analyzed 417 patients > 45 years with ALL in first complete remission who underwent a matched sibling or unrelated allo-HSCT and compared outcomes between fludarabine/busulfan (FLUBU, n = 127), fludarabine/melphalan (FLUMEL, n = 190), and fludarabine-TBI (FLUTBI, n = 100) conditioning. At 2 years, there were no differences between the groups in terms of cumulative incidence (CI) of relapse (40% for FLUBU vs 36% for FLUMEL vs 41% for FLUTBI, p = 0.21); transplant-related mortality (TRM) (18% for FLUBU, 22% for FLUMEL, 14% for FLUTBI, p = 0.09); overall survival (55% for FLUBU, 50% for FLUMEL, 60% for FLUTBI, p = 0.62) or leukemia-free survival (43% for FLUBU, 42% for FLUMEL, 45% for FLUTBI, p = 0.99), but GVHD-relapse-free survival was significantly lower in the FLUTBI group than FLUBU and FLUMEL group (18% vs 35% vs 28%, p = 0.02). However, this difference was lost in the multivariate analysis when adjusted for the in vivo T-cell depletion. Finally, the FLUMEL regimen was shown to be an independent risk factor for a higher TRM (HR 1.97, 95% CI 1.05-3.72, p = 0.04). We conclude that the three most popular RIC regimens yield similar transplant outcomes.
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Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes
Martino, R., Henseler, A., van Lint, M., Schaap, N., Finke, J., Beelen, D., Vigouroux, S., Alessandrino, E. P., Mufti, G. J., Veelken, J. H., et al
Bone Marrow Transplantation. 2017;52(8):1107-1112
Abstract
This study shows the long-term updated outcomes of a multicenter retrospective study which analyzed 843 patients with myelodysplastic syndrome (MDS) who underwent transplantation with an HLA-identical sibling donor with either reduced-intensity conditioning (RIC) in 213 patients, or standard myeloablative conditioning (MAC) in 630 patients. In multivariate analysis, the 13-year relapse rate was significantly increased after RIC (31% after MAC vs 48% in RIC; HR, 1.5; 95% CI, 1.1-1.9; P=0.04), but with no differences in overall survival (OS) (30% after MAC vs 27% in RIC; P=0.4) and PFS (29 vs 21%, respectively, P=0.3). Non-relapse mortality was higher in MAC (40 vs 31%; P=0.1), especially in patients older than 50 years (50 vs 33%, P<0.01). In addition, long-term follow-up confirms the importance of other variables on 13-year OS, mainly MDS risk category, disease phase, cytogenetics and receiving a high donor cell dose, irrespective of the conditioning regimen used.