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1.
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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2.
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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3.
Comorbidities in recipients of low transplant conditioning intensity regimens for acute myeloid leukemia: an ALWP EBMT study
Fein, J. A., Shouval, R., Galimard, J. E., Labopin, M., Socié, G., Finke, J., Cornelissen, J. J., Malladi, R., Itälä-Remes, M., Chevallier, P., et al
Blood advances. 2023
Abstract
Older age and high burden of comorbidities often drive selection of low-intensity conditioning regimens in allogeneic-hematopoietic stem cell transplantation (HSCT) recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of non-relapse mortality (NRM) in patients receiving low-intensity regimens. In a retrospective analysis of adults (≥ 18 years) transplanted for acute myeloid leukemia (AML) in first complete remission (CR) between 2008-2018, we studied recipients of low-intensity regimens as defined by the Transplantation Conditioning Intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1,663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR] 1.54 [95% CI 1.13, 2.09] and 1.69 [1.02, 2.82], respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel disease were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches.
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Allogeneic Stem Cell Transplantation in Patients >40 Years of Age With Acute Lymphoblastic Leukemia: Reduced Intensity Versus Myeloablative Conditioning
Sijs-Szabo, A., Dinmohamed, A. G., Versluis, J., van der Holt, B., Bellido, M., Hazenberg, M. D., van Gelder, M., Schaap, N. P. M., Meijer, E., van der Wagen, L. E., et al
Transplantation. 2023
Abstract
BACKGROUND The outcome in older patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory due to high relapse and nonrelapse mortality (NRM) rates. Allogeneic stem cell transplantation (alloHSCT) as postremission therapy has an important role in reducing relapse rate, albeit its application is limited in older adult patients due to alloHSCT-related morbidity and mortality. Reduced-intensity conditioning (RIC) alloHSCT has been developed as a less toxic conditioning regimen, but comparative studies with myeloablative conditioning (MAC) are limited in patients with ALL. METHODS In this retrospective study, RIC-alloHSCT (n = 111) was compared with MAC-alloHSCT (n = 77) in patients aged 41 to 65 y with ALL in first complete remission. MAC was predominantly applied by combining high-dose total body irradiation and cyclophosphamide, whereas RIC mainly consisted of fludarabine and 2 Gy total body irradiation. RESULTS Unadjusted overall survival was 54% (95% confidence interval [CI], 42%-65%) at 5 y in MAC recipients compared with 39% (95% CI, 29%-49%) in RIC recipients. Overall survival and relapse-free survival were not significantly associated with type of conditioning after adjusted for the covariates age, leukemia risk status at diagnosis, donor type, and donor and recipient gender combination. NRM was significantly lower after RIC (subdistribution hazard ratio: 0.41, 95% CI, 0.22-0.78; P = 0.006), whereas relapse was significantly higher (subdistribution hazard ratio: 3.04, 95% CI, 1.71-5.40; P < 0.001). CONCLUSIONS Collectively, RIC-alloHSCT has resulted in less NRM, but it was also found to be associated with a significantly higher relapse rate. These results suggest that MAC-alloHSCT may provide a more effective type of consolidation therapy for the reduction of relapse and that RIC-alloHSCT may be restricted to patients at higher risk for NRM.
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Outcome of human umbilical cord blood stem cell transplantation (CBT) for acute myeloid leukemia in patients achieving first complete remission after one versus two induction courses: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Nagler, A., Labopin, M., Cornelissen, J. J., Forcade, E., Chevallier, P., Fegueux, N., Sierra, J., Desmier, D., Labussière-Wallet, H., Byrne, J. L., et al
Bone marrow transplantation. 2022
Abstract
We compared transplantation outcomes of adult patients with AML that underwent cord blood transplantation (CBT) in CR1 following 1 versus 2 induction courses. Study included 325 patients, 243 (75%) with 1 and 82 (25%) with 2 induction courses. Engraftment was lower for patients achieving CR1 after 1 vs. 2 induction courses: 91% vs. 99% (p = 0.02). Incidence of acute GVHD was similar, 38% and 36% (p = 0.81), as was 2-year chronic GVHD at 23.4% and 27.5%, respectively (p = 0.65). Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were not statistically different between patients achieving CR1 with 1 vs. 2 induction courses with 23% vs. 24% (p = 0.87), 25% vs. 30% (p = 0.4), 52% vs. 46% (p = 0.3), 59% vs. 50% (p = 0.2), and 44% vs. 41% (p = 0.66), respectively. Results were confirmed by multivariable analysis, NRM (hazard ratio (HR) = 1.1; 95% CI, 0.6-1.8, p = 0.7), RI (HR = 1.4; 95% CI, 0.9-2.3, p = 0.1), LFS (HR = 1.3; 95% CI, 0.9-1.8, p = 0.2), OS (HR = 1.3; 95% CI, 0.9-1.9, p = 0.1), and GRFS (HR = 1.1; 95% CI, 0.8-1.5, p = 0.5). Overall, outcomes of AML patients undergoing CBT in CR1 achieved after 1 or 2 induction courses are similar.
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The added value of multi-state modelling in a randomized controlled trial: The HOVON 102 study re-analyzed
Bakunina, K., Putter, H., Versluis, J., Koster, E. A. S., van der Holt, B., Manz, M. G., Breems, D. A., Gjertsen, B. T., Cloos, J., Valk, P. J. M., et al
Cancer Medicine. 2022;11(3):630-640
Abstract
Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events.
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Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients
Spyridonidis, A., Labopin, M., Savani, B. N., Niittyvuopio, R., Blaise, D., Craddock, C., Socie, G., Platzbecker, U., Beelen, D., Milpied, N., et al
Bone marrow transplantation. 2020
Abstract
To address limitations of the currently used reduced-intensity/myeloablative conditioning (RIC/MAC) classification scheme we aimed to develop a tool that can capture more standardized the conditioning intensity of allogeneic hematopoietic cell transplantation (HCT). We assigned intensity weight scores for frequently used conditioning regimen components and used their sum to generate the transplant conditioning intensity (TCI) score. We retrospectively tested the impact of TCI on 8255 adult (45-65 years) acute myeloid leukemia patients who underwent HCT in first complete remission. A Cox model for early nonrelapse mortality (NRM) yielded a 3-group TCI risk scheme (low, intermediate, high) with respective TCI scores of [1-2], [2.5-3.5] and [4-6]. On multivariate modeling, TCI grouping was highly and better predictive for early (day 100 and 180) NRM, 2-year NRM and relapse (REL) as compared with the RIC/MAC classification. Validation was done on 200 bootstrap samples. Moreover, TCI scoring enabled the identification of a distinct subgroup of RIC and MAC conditioning regimens with an intermediate TCI [2.5-3.5] score that had identical outcomes and which are frequently referred as "reduced toxicity conditioning". TCI scheme provides an improvement of the RIC/MAC classification. We propose TCI as a new tool to define and measure the conditioning regimen intensity.
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Allogeneic haemopoietic transplantation for acute myeloid leukaemia in second complete remission: a registry report by the Acute Leukaemia Working Party of the EBMT
Gilleece, M. H., Labopin, M., Savani, B. N., Yakoub-Agha, I., Socie, G., Gedde-Dahl, T., Blaise, D., Byrne, J. L., Craddock, C., Cornelissen, J. J., et al
Leukemia. 2019
Abstract
Allogeneic haemopoietic cell transplant (allo-HCT) may be curative in acute myeloid leukaemia (AML) in second complete remission (CR2) but the impact of reduced intensity (RIC) versus myeloablative conditioning (MAC) is uncertain. The Acute Leukaemia Working Party of the European Society for Blood and Bone Marrow Transplantation Registry studied an AML CR2 cohort characterised by age ≥ 18 years, first allo-HCT 2007-2016, available cytogenetic profile at diagnosis, donors who were matched family, volunteer unrelated with HLA antigen match 10/10 or 9/10 or haplo-identical. The 1879 eligible patients included 1010 (54%) MAC allo-HCT recipients. In patients <50 years (y), two year outcomes for MAC vs RIC allo-HCT were equivalent with leukaemia-free survival (LFS) 54% for each, overall survival (OS), 61% vs 62%, non-relapse mortality (NRM) 18% vs 15% and graft versus host disease relapse-free survival (GRFS) 38% vs 42%. In patients ≥50 y, 2 y outcomes for MAC vs RIC allo-HCT were equivalent for LFS 52% vs 49%, OS 58% vs 55% and GRFS 42.4% vs 36%. However, NRM was significantly inferior after MAC allo-HCT, 27% vs 19% (P = 0.01) despite worse cGVHD after RIC-allo (32% vs 39%). These data support the need for ongoing prospective study of conditioning intensity and GVHD mitigation in AML.
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Impaired thymopoiesis predicts for a high risk of severe infections after reduced intensity conditioning without anti-thymocyte globulin in double umbilical cord blood transplantation
Duinhouwer, L. E., Beije, N., van der Holt, B., Rijken-Schelen, A., Lamers, C. H., Somers, J., Braakman, E., Cornelissen, J. J.
Bone marrow transplantation. 2018
Abstract
Umbilical cord blood stem cell transplantation (UCBT) is associated with retarded hematopoietic recovery and immune reconstitution and a high infection-related morbidity and mortality, especially after conditioning including anti-thymocyte globulin (ATG). However, data on immune recovery, incidence of infections, and outcome in double UCBT (dUCBT) recipients receiving an ATG-free reduced intensity conditioning (RIC) are lacking. In this study, recovery of lymphocyte subsets, thymopoiesis, and its association with severe infections and clinical outcome was assessed in a group of 55 recipients of a dUCBT ATG-free RIC regimen. T cell recovery was severely protracted in the majority of patients. However, T cell receptor excision circle TREC(+) T cells were detectable in 62% of patients at 3 months post-transplantation. A total of 128 common toxicity criteria grade 3-4 infections were observed in the first year post-transplantation. Non-relapse mortality at 12 months post-transplant was 16%, of which 78% infectious mortality. One-year overall survival was 73%. Patients who failed to recover thymopoiesis at 3 months post-transplantation were at a 3.3-fold higher risk of subsequent severe grade 3-4 infections.
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10.
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.