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The impact of pre-transplantation diabetes and obesity on acute graft-versus-host disease, relapse and death after allogeneic hematopoietic cell transplantation: a study from the EBMT Transplant Complications Working Party
Gjærde, L. K., Ruutu, T., Peczynski, C., Boreland, W., Kröger, N., Blaise, D., Schroeder, T., Peffault de Latour, R., Gedde-Dahl, T., Kulagin, A., et al
Bone marrow transplantation. 2023
Abstract
Obesity and diabetes can modulate immune responses, which may impact allogeneic HCT outcomes and GvHD. From the EBMT registry, we included 36,539 adult patients who underwent allogeneic HCT for a hematological malignancy between 2016 and 2020. Of these, 5228 (14%) had obesity (BMI ≥ 30 kg/m(2)), 1415 (4%) had diabetes (requiring treatment with insulin or oral hypoglycemics), and 688 (2%) had obesity + diabetes pre-transplantation. Compared with patients without diabetes or obesity, the hazard ratio (HR) of grade II-IV acute GvHD was 1.00 (95% confidence interval [CI] 0.94-1.06, p = 0.89) for patients with obesity, 0.95 (CI 0.85-1.07, p = 0.43) for patients with diabetes, and 0.96 (CI 0.82-1.13, p = 0.63) for patients with obesity + diabetes. Non-relapse mortality was higher in patients with obesity (HR 1.08, CI 1.00-1.17, p = 0.047), diabetes (HR 1.40, CI 1.24-1.57, p < 0.001), and obesity + diabetes (HR 1.38, CI 1.16-1.64, p < 0.001). Overall survival after grade II-IV acute GvHD was lower in patients with diabetes (HR 1.46, CI 1.25-1.70, p < 0.001). Pre-transplantation diabetes and obesity did not influence the risk of developing acute GvHD, but pre-transplantation diabetes was associated with poorer survival after acute GvHD.
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Impact of Allele-Level HLA-Matching on Outcomes after Double Cord Blood Transplantation in Adults with Malignancies
Fatobene, G., Mariano, L., Volt, F., Moreira, F., Conelissen, J., Furst, S., Daguindau, E., Sirvent, A., Peffault de Latour, R., Rafii, H., et al
Blood advances. 2023
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Editor's Choice
Abstract
In single unrelated cord blood transplantation (UCBT), an increasing number of HLA allele mismatches (MM) has been associated with inferior overall survival (OS) attributed to higher transplant-related mortali-ty (TRM). Previous studies on the role of allele-level HLA matching following double UCBT (dUCBT) showed conflicting results. Herein we report the impact of allele-level HLA matching on outcomes of a large dUCBT cohort . We included 963 adults with hematologic malignancies, with available allele-level HLA matching at HLA-A, -B, -C and -DRB1, receiving dUCBT between 2006-2019. Assignment of donor-recipient HLA match was performed considering the unit with the highest disparity with the recipient. 392 patients received dUCBT with 0-3 and 571 with ≥4 allele MM. Day-100 and 4-year TRM were 10% and 23%, for recipients of dUCBT with 0-3 MM compared to 16% and 36% for those with ≥4 MM (HR 1.58, p=.002; and HR 1.54, p=.002), respectively. Higher degree of allele MM was also associated with worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0-3 MM had a 4-year OS of 54% versus 43% for those with ≥4 MM (HR 1.40, p=.005). The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses. Our results confirm that allele-level HLA typing is a significant factor for OS following dUCBT and units with ≥4 MM (≤4/8 HLA-matched) should be avoided if possible.
PICO Summary
Population
Adults with haematologic malignancies, receiving double cord blood transplantation (dUCBT) with available allele-level HLA matching at HLA-A, -B, -C and -DRB1, identified from the Eurocord/EBMT registry (n=963)
Intervention
Transplant with 0-3 allele mismatch (MM) (n=392)
Comparison
Transplant with ≥4 allele MM (n=571)
Outcome
Day-100 and 4-year transplant-related mortality were 10% and 23%, for recipients of dUCBT with 0-3 MM compared to 16% and 36% for those with ≥4 MM (HR 1.58, p=.002; and HR 1.54), respectively. Higher degree of allele MM was also associated with worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0-3 MM had a 4-year OS of 54% versus 43% for those with ≥4 MM (HR 1.40, p=.005). The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses.
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Cord blood transplantation for adult lymphoid neoplasms in Europe and Japan
Watanabe, M., Kanda, J., Volt, F., Ruggeri, A., Suzuki, R., Rafii-Elayoubi, H., Kimura, F., Cappelli, B., Kondo, E., Scigliuolo, G. M., et al
Blood advances. 2023
Abstract
With the aim of identifying the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study between European and Japanese registries. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n=192; double CBT, n=304; Japan: single CBT, n=1150) in 2000-2017 were analyzed. The number of patients with Hodgkin's lymphoma was higher in Europe (26% vs 5%) while that with mature T/NK-cell neoplasms was higher in Japan (20% vs 35%). The Japanese cohort comprised more elderly patients (>=50) (59% vs 39%) with higher refined disease risk index (rDRI) (high-very high: 49% vs 14%). High-very high rDRI (vs. low rDRI) was associated with inferior OS in common (Europe: HR 1.87 p=0.001; Japan: HR 2.34, p<0.001) with higher progression/relapse risks (Europe: HR 2.04, p=0.007; Japan: HR 2.96, p<0.001). Total body irradiation (TBI)-containing conditioning regimens contributed to superior OS both in Europe (vs TBI-RIC, non TBI-RIC: HR 1.93, p<0.001; non TBI-MAC: HR 1.90, p=0.003) and in Japan (non TBI-RIC: HR 1.71, p<0.001; non TBI-MAC: HR 1.50, p=0.007). The impact of HLA mismatches (>=2) on OS differed (Europe: HR 1.52, p=0.007; Japan: HR 1.18, p=0.107). Despite the different patient-disease-transplant characteristics, poor survival of patients receiving CBT for lymphoid neoplasms, especially in those with high rDRI was observed in both registries. The different impact of HLA mismatches on survival in the two registries calls attention to the fundamental differences among these populations. TBI should be considered in conditioning regimens.
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Outcomes of subsequent neoplasms after umbilical cord blood transplantation in Europe
Rafii, H., Ruggeri, A., Kenzey, C., Sanz, J., Peffault de Latour, R., Esquirol, A., Michel, G., Chevallier, P., Rubio, M. T., Cornelissen, J. J., et al
Blood advances. 2022
Abstract
Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell transplantion. We performed a retrospective analysis of SNs in a cohort of 10358 recipients of umbilical cord blood transplantation (UCBT) reported to Eurocord/EBMT registries from 1988 to 2018. A total of 233 patients developed SNs. Median age at UCBT was 31 years (y) (0.3-69), and 84 were pediatric patients. Indications for UCBT were malignant hematological diseases in 199 patients (85%). Three groups of SNs were observed. Post-transplant lymphoproliferative disorders (PTLD) were reported in 145 patients in a median of 4 months after UCBT. Of these, 9/145 patients died from relapse, 83/145 from PTLD, and 24/145 from transplant-related causes. At last follow-up, 29/145 were alive; 5y-overall survival (OS) after PTLD diagnosis was 21±3%. Acute leukemia / myelodysplasia (AL/MDS) was diagnosed in 23 patients in a median of 28 months after UCBT and included 3 donor-cell AL. Four of 23 patients died from relapse of primary disease, 8/23 from progression of SNs, and 4/23 from TRM. Seven patients were alive at last follow-up; 5y-OS after AL/MDS diagnosis was 36±10%. Solid tumors (ST) were reported in 65 patients in a median of 54 months after UCBT. Most common tumor sites were lung, thyroid, bone and soft tissue. A total of 33/65 patients died (26 due to ST, 6 to relapse of primary disease, 1 cause missing). At last follow-up, 32/65 patients were alive; 5y-OS after the diagnosis of ST was 51±6%. In conclusion, despite their poor outcomes, SNs that occur after UCBT are extremely rare. Identification of associated risk factors and early detection may help to improve OS.
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Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study
Mohty, M., Blaise, D., Peffault de Latour, R., Labopin, M., Bourhis, J. H., Bruno, B., Ceballos, P., Detrait, M., Gandemer, V., Huynh, A., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.
PICO Summary
Population
Adults and children receiving defibrotide for treatment or prophylaxis of veno-occlusive disease / sinusoidal obstruction syndrome (VOD/SOS) between July 2014 to March 2020 at 53 French HCT centres (n=798)
Intervention
Defibrotide for severe/very severe VOD/SOS (n=251); Defibrotide for mild/moderate VOD/SOS (n=81)
Comparison
Defibrotide for VOD/SOS prophylaxis (n=381)
Outcome
In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated complete remission (CR) at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%.
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6.
Azithromycin promotes relapse by disrupting immune and metabolic networks after allogeneic stem cell transplantation
Vallet, N., Le Grand, S., Bondeelle, L., Hoareau, B., Corneau, A., Bouteiller, D., Tournier, S., Lew-Derivry, L., Bohineust, A., Tourret, M., et al
Blood. 2022
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Editor's Choice
Abstract
Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematological malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients' samples to decipher immune alterations associated with azithromycin intake and post-transplant relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T cells cytotoxicity against tumor cells and impaired T cells metabolism through glycolysis inhibition, mitochondrial genes downregulation, and immunomodulatory genes upregulation, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies.
PICO Summary
Population
Participants with haematological malignancies enrolled in the ALLOZITHRO trial (n=240)
Intervention
Azithromycin 250 mg x 3/week (n=123)
Comparison
Placebo (n=117)
Outcome
Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T cells cytotoxicity against tumor cells and impaired T cells metabolism through glycolysis inhibition, mitochondrial genes downregulation, and immunomodulatory genes upregulation, notably SOCS1.
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Humoral and cellular responses to SARS-CoV-2 BNT162b2 vaccination in allogeneic hematopoietic stem cell transplantation recipients
Cuffel, A., Maylin, S., Le Buanec, H., Delaugerre, C., Minier, M., Bergerat, D., Merandet, M., Cassius, C., Peffault de Latour, R., Le Goff, J., et al
Vaccine. 2022
Abstract
Previous studies reporting the response to SARS-CoV-2 mRNA vaccination in alloHSCT recipients used serological and/or cellular assays, but no study has evaluated vaccine-induced neutralizing antibodies. We prospectively studied 28 alloHSCT recipients who received two BNT162b2 doses. Two patients groups were defined according to time from alloHSCT and immunosuppressive treatment, and had different baseline immunologic status. Study end-point was the evaluation of humoral and cellular responses one month after the second vaccine. All patients seroconverted. Anti-S IgG levels and neutralizing antibodies percentages were not significantly different between both groups. Using IFNγ ELISpot assay, five patients showed a strong increase, without correlation with the humoral response. Using flow cytometry lymphocyte proliferation assay, 14 patients exhibited responding T cells, without difference between both groups or correlation with anti-S IgG levels. A few low serological responders had a detectable CD4 + T cell proliferative response. This finding should be confirmed in a larger cohort.
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8.
Immune landscape after allo-HSCT: TIGIT and CD161-expressing CD4 T cells are associated with subsequent leukemia relapse
Gournay, V., Vallet, N., Peux, V., Vera, K., Bordenave, J., Lambert, M., Corneau, A., Michonneau, D., Peffault de Latour, R., Caillat-Zucman, S., et al
Blood. 2022
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Abstract
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the most effective treatment for selected patients with acute myeloid leukemia (AML) and relies on a "graft-versus-leukemia" effect (GVL) where donor T lymphocytes mediate control of malignant cell growth. However, relapse remains the major cause of death after allo-HSCT. In various malignancies, several immunoregulatory mechanisms have been shown to restrain antitumor immunity, including ligand-mediated engagement of inhibitory receptors on effector cells, and induction of immunosuppressive cell-subsets such as regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). While relapse after HSCT remains a major therapeutic challenge, immunoregulatory mechanisms involved in restraining the GVL effect need to be better deciphered in humans. We used mass cytometry to comprehensively characterize circulating leukocytes in two cohorts of patients after allo-HSCT. We first longitudinally assessed various immunoregulatory parameters highlighting specific trends, such as opposite dynamics between MDSCs and Tregs. More generally, the immune landscape was rather stable from month-3 to 6, while many variations occurred from month-6 to 12 post-HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1-year post-HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 post-HSCT were distinct features significantly associated with subsequent AML relapse in a second cross sectional cohort. Altogether, these data provide global insights into the immunoregulatory landscape reconstitution following HSCT, and highlight non-canonical inhibitory receptors associated with relapse, which could open the path towards new prognostic tools or therapeutic targets to restore subverted anti-AML immunity.
PICO Summary
Population
Adults with acute myeloid leukaemia or myelodysplastic syndrome, undergoing allogeneic transplant
Intervention
Measurement of peripheral blood mononuclear cells at months 3, 6 and 12 after transplant (n=37)
Comparison
Comparison cohort of healthy volunteers (n=20)
Outcome
More generally, the immune landscape was rather stable from month-3 to 6, while many variations occurred from month-6 to 12 post-HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1-year post-HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 post-HSCT were distinct features significantly associated with subsequent AML relapse in a second cross sectional cohort.
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Prospective external validation of biomarkers to predict acute graft-versus host disease severity
Robin, M., Porcher, R., Michonneau, D., Taurines, L., Sicre de Fontbrune, F., Xhaard, A., Oriano, B., Sutra Del Galy, A., Peffault de Latour, R., Socié, G., et al
Blood advances. 2022
Abstract
Acute GVHD is still the major contributor to comorbidities and mortality after allogeneic hematopoietic stem cell transplantation (HSCT. The use of plasmatic biomarkers to predict early outcomes have been advocated in the last decade. The purpose of this prospective non interventional study was to test the ability of panels including 7 biomarkers (Elafin, HGF, IL2RA, IL8, REG3, ST2 and TNFRI), to predict Day 28 (D28)-complete response to steroid, D180-overall survival (OS) and D180-non-relapse mortality (NRM). Using previous algorithms developed by the Ann Arbor / MAGIC consortium, 204 patients with acute GVHD were prospectively included and biomarkers were measured at GVHD onset for all of them. Initial GVHD grade and bilirubin level were significantly associated with all those outcomes. After adjustment on clinical variables, biomarkers were associated with survival and NRM. In addition to clinical variables, biomarkers slightly improved the prediction of overall survival and NRM (concordance [C] and net reclassification indexes). The potential benefit of adding biomarkers panel to clinical parameters was also investigated by decision curve analyses. The benefit of adding biomarkers to clinical parameters was however marginal for the D28 non-response and mortality endpoints.
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Impact of the SARS-CoV-2 pandemic on hematopoietic cell transplantation and cellular therapies in Europe 2020: a report from the EBMT activity survey
Passweg, J. R., Baldomero, H., Chabannon, C., Corbacioglu, S., de la Cámara, R., Dolstra, H., Glass, B., Greco, R., Mohty, M., Neven, B., et al
Bone marrow transplantation. 2022;:1-11
Abstract
In 2020, 45,364 HCT in 41,016 patients, 18,796 (41%) allogeneic and 26,568 (59%) autologous in 690 centers were reported. Changes observed were as follows: total number of HCT -6.5%, allogeneic HCT -5.1%, autologous HCT -7.5%, and were more pronounced in non-malignant disorders for allogeneic HCT and in autoimmune disease for autologous HCT. Main indications were myeloid malignancies 10,441 (25%), lymphoid malignancies 26,120 (64%) and non-malignant disorders 2532 (6%). A continued growth in CAR-T cellular therapies to 1874 (+65%) patients in 2020 was observed. In allogeneic HCT, the use of haploidentical donors increased while use of unrelated and sibling donors decreased. Cord blood HCT increased by 11.7% for the first time since 2012. There was a significant increase in the use of non-myeloablative but a drop in myeloablative conditioning and in use of marrow as stem cell source. We interpreted these changes as being due to the SARS-CoV-2 pandemic starting early in 2020 in Europe and provided additional data reflecting the varying impact of the pandemic across selected countries and larger cities. The transplant community confronted with the pandemic challenge, continued in providing patients access to treatment. This annual report of the EBMT reflects current activities useful for health care planning.