-
1.
An endothelial proinflammatory phenotype precedes the development of the engraftment syndrome after autologous Hct
Moreno-Castaño, A. B., Palomo, M., Torramadé-Moix, S., Martinez-Sanchez, J., Ramos, A., Molina, P., Pino, M., Gómez-Ramírez, P., Bonastre, L., Solano, M. T., et al
Bone marrow transplantation. 2022
Abstract
Engraftment syndrome (ES) is a common complication after autologous hematopoietic cell transplantation (auto-HCT) whose pathophysiological substrate remains unclear. We investigated whether endothelial damage could contribute to ES. Circulating ECs-damage biomarkers were measured in plasma from patients with (ES; n = 14) or without ES (non-ES; n = 20), collected at different time points: before HCT, 5 (S5) and 10 days (S10) after HCT, and at either the ES onset (SON) or the discharge day (SDIS). Also, cultured endothelial cells (ECs) were exposed to serum samples, obtained at the same points, to evaluate changes in ECs-activation (ICAM-1, VE-Cadherin) biomarkers, the reactivity of ECs towards leukocytes, and activation of intracellular signaling proteins related to inflammation (p38MAPK) and proliferation (Erk1/2). Results showed that circulating VWF, sTNFR1 and sVCAM-1 levels were higher in ES patients at all the points assessed, especially at SON. In vitro results showed an increased ICAM-1 expression on ECs exposed to ES samples vs. non-ES samples, especially to S5, with elevated leukocyte adhesion. Also, a lower VE-Cadherin expression and an increased phosphorylation of p38MAPK and Erk1/2 proteins were observed in ECs exposed to ES vs. non-ES samples. Our results indicate that endothelial activation precedes ES development and could be one of its pathophysiological substrates.
-
2.
[Crohn's disease and autologous hemapoietic cell transplantation: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]
Puyade, M., Treton, X., Alric, L., Badoglio, M., Castilla Llorente, C., Fotsing, G., Marjanovic, Z., Rovira, M., Terriou, L., Torregrosa Díaz Jose, M., et al
Bulletin du cancer. 2020
Abstract
Crohn's Disease (CD) is an auto-inflammatory disease, which may involve the entire gastro-intestinal tract. CD is diagnosed on several clinical, biological, endoscopic and histological criteria. First line therapy is based on oral or iv steroids. In case of steroids dependence or resistance, several types of immunosuppressive or immunomodulating therapies are available: classical antimetabolites (thiopurines or methotrexate) or monoclonal antibodies against TNFα, against interleukin 12/23 or against integrin. Nonetheless, Crohn's disease may remain active despite the use of several lines of therapy. In such cases, autologous hematopoietic cell transplantation (AHCT) is an effective therapeutic option in highly selected CD patients with specific criteria. The MATHEC-SFGM-TC Good Clinical Practice Guidelines (GCPG) were developed by a multidisciplinary group of experts including gastroenterologists, hematologists and members of the reference center for stem cell therapy in auto-immune diseases (MATHEC), including members of the French groupe d'étude thérapeutique des affections inflammatoires du tube digestif(GETAID) under the auspices of the French speaking Society of bone marrow transplantation and cellular therapy (SFGM-TC). The aim of the present guidelines is to define the eligibility criteria for CD patients when candidates to AHCT, the procedures for mobilization of hematopoietic stem cell (HSC), conditioning regimen and standardized follow-up after AHCT including monitoring of gastroenterological treatments during AHCT and thereafter throughout all follow-up.
-
3.
Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party
Henes, J., Oliveira, M. C., Labopin, M., Badoglio, M., Scherer, H. U., Del Papa, N., Daikeler, T., Schmalzing, M., Schroers, R., Martin, T., et al
Haematologica. 2020
-
-
-
Free full text
-
Editor's Choice
Abstract
Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multi-center prospective non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult systemic sclerosis patients undergoing a first autologous hematopoietic stem cell transplantation between December 2012 and February 2016 were prospectively included in the study. Primary endpoint was progression free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty systemic sclerosis patients were included. Median follow-up duration was 24 (6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulins conditioning for all, with CD34+ selection in 35 patients. At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (p< 0.001). By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival (Hazard ration 3.32) and 1.77, respectively). CD34+-selection was associated with better response (Hazard ration: 0.46). This study confirms the efficacy of autologous stem cell transplantation in real-life practice for severe systemic sclerosis using non myeloablative conditioning. Careful cardio-pulmonary assessment to identify organ involvement at patient referral, reduced cyclophosphamide doses and CD34+ selection may improve outcomes. The study was registered at ClinicalTrials.gov: NCT02516124.
PICO Summary
Population
Adult patients with severe systemic sclerosis (n=80)
Intervention
Autologous haematopoietic stem cell transplantation with cyclophosphamide plus antithymocyte globulins conditioning
Comparison
None
Outcome
At 2 years, progression free survival was 81.8%, overall survival was 90%, response was 88.7% and incidence of progression was 11.9%. The 100 days non-relapse mortality was 6.25% (n=5) with four deaths from cardiac event, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time. By multivariate analysis, baseline skin score >24 and older age at transplant were associated with lower progression free survival. CD34+-selection was associated with better response.
-
4.
Predicting mortality after autologous transplant: Development of a novel risk score
Berro, M., Chhabra, S., Pinana, J. L., Arbelbide, J., Rivas, M. M., Basquiera, A. L., Vitriu, A., Requejo, A., Milovic, V., Yantorno, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
There have been several efforts to predict mortality after autologous stem cell transplantation (ASCT), such as the Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI), described for allogeneic-SCT and validated for ASCT, however there is no composite score in the setting of ASCT combining comorbidities with other clinical characteristics. Our aim is to describe a comprehensive score combining comorbidities with other clinical factors and to analyze the impact of this score on non-relapse mortality (NRM), overall survival (OS) and early morbidity end-points (mechanical ventilation, shock or dialysis) after ASCT. For the training cohort, we retrospectively reviewed data of 2068 adult patients who received an ASCT in Argentina (10/2002-06/2017) for multiple myeloma or lymphoma. For the validation cohort, we analyzed 2168 ASCT performed in the Medical College of Wisconsin and Spanish stem cell transplant group (GETH) (01/2012-12/2018). We first performed a multivariate analysis for NRM in order to select and assigned weight to the risk factors included in the score (male patients, age 55-64 and ≥65 years, HCT-CI ≥3, HL and NHL). The hazard ratio for NRM increased proportionally with the score. Patients were grouped as low risk (LR) with a score 0-1 (686, 33%), intermediate risk (IR) score 2-3 (1109, 53%), high risk (HR) score 4 (198, 10%) and very high risk (VHR) score ≥5 (75, 4%). The score was associated with a progressive increase in all the early morbidity endpoints. Moreover, the score was significantly associated with early NRM (day 100: 1.5% vs 2.4% vs 7.6% vs. 17.6%) as well as long term (1-3 years 1.8-2.3% vs. 3.8-4.9% vs. 11.7-14.5% vs. 25.0-27.4% respectively, p<0.0001) and OS (1-5 years 94-73% vs. 89-75% vs. 76-47% vs. 65-52% respectively, p<0.0001). The score was validated in an independent cohort (N=2168) and was significantly associated with early and late events. In conclusion, we developed and validated a novel score predicting NRM and OS in two large cohorts of more than 2000 autologous transplant patients. This tool can be useful for tailoring conditioning regimens or defining risk for transplant programs decision-making.
-
5.
The avoidance of G-CSF and the addition of prophylactic corticosteroids after autologous stem cell transplantation for multiple myeloma patients appeal for the at-home setting to reduce readmission for neutropenic fever
Rodríguez-Lobato, L. G., Martínez-Roca, A., Castaño-Díez, S., Palomino-Mosquera, A., Gutiérrez-García, G., Pedraza, A., Suárez-Lledó, M., Rovira, M., Martínez, C., Fernández de Larrea, C., et al
PloS one. 2020;15(11):e0241778
Abstract
BACKGROUND Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT. METHODS Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning +1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT. RESULTS The incidence of NF among the groups was reduced (64%, 44%, and 24%; P<0.001), with a non-significant decrease in hospital readmissions as well (12%, 6%, and 2%; P = 0.07). The most important variables identified for NF were: HCT-CI >2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P<0.001); and for hospital readmission: age =60 years (OR 14.6; P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05). CONCLUSIONS G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT. This approach should be explored in a prospective randomized clinical trial.
-
6.
Impact of intensifying primary antibiotic prophylaxis in at-home autologous stem cell transplantation program for lymphoma patients
Rodriguez-Lobato, L. G., Martinez-Roca, A., Moreno, D. F., Gutierrez-Garcia, G., Suarez-Lledo, M., Rovira, M., Martinez, C., Rosinol, L., Almeida Jorge, A. S., Pedraza, A., et al
Leukemia & lymphoma. 2020;:1-10
Abstract
Despite the use of fluoroquinolone (FQ) prophylaxis, neutropenic fever (NF) is the most frequent cause of hospital readmission in ambulatory care programs for patients treated with autologous stem cell transplantation (ASCT). We analyzed the impact of intensifying primary prophylaxis with the addition of piperacillin/tazobactam (PT) to FQ. Between January 2002 and August 2018, 154 lymphoma patients conditioned with BEAM were included (40% received ceftriaxone (Ct) plus FQ and 60% PT plus FQ). NF and hospital readmission were required in 84 vs. 41% (p < .0001) and 12 vs. 1% (p = .007) of patients within the Ct and PT groups, respectively. The multivariate analysis showed that PT plus FQ retained its independent protective factor for NF (odds ratio (OR): 0.13; p < .001) and for hospital readmission (OR: 0.07; p = .01). The use of PT and FQ prophylaxis may effectively prevent episodes of NF and hospitalizations in lymphoma patients managed in our at-home ASCT care model.
-
7.
Improving security of autologous hematopoietic stem cell transplant in patients with light-chain amyloidosis
Gutierrez-Garcia, G., Cibeira, M. T., Rovira, M., Fernandez de Larrea, C., Tovar, N., Rodriguez-Lobato, L. G., Rosinol, L., Marin, P., Solano-Vega, J., Suarez-Lledo, M., et al
Bone marrow transplantation. 2019
Abstract
Autologous stem cell transplant (ASCT) has demonstrated to be an effective treatment for patients with light-chain (AL) amyloidosis. However, a high transplant-related mortality (TRM) rate was reported in previous series of patients and questioned the role of transplant in this disease. Recently, experienced groups have shown a significant TRM decrease that has been attributed to an accurate selection of patients. Moreover, application of several supportive measures has decreased toxicity over amyloid-involved organs. We analyzed a series of 66 patients with AL amyloidosis, who underwent ASCT at a single institution and evaluated the impact of these measures beyond patient selection. Four temporary groups were established: group-A (non-selection plus post-transplant G-CSF use) with 29 patients, group-B (selection) with 13, group-C (selection and G-CSF avoidance) with 14, and group-D (selection, G-CSF avoidance and corticosteroid's prophylaxis) with 10. A decreasing TRM was observed over time from group-A (38%), to group-D (0%); p = 0.02. We also observed a progressive increase of three-year OS from 62% in group-A to 100% in group-D; p = 0.049. On the multivariate analysis, cardiac involvement was the only independent predictor of survival. Therefore, tailored selection policy together with transplant supportive measures have allowed ASCT to be a safe procedure in AL amyloidosis.
-
8.
Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases: updated guidelines and recommendations from the EBMT Autoimmune Diseases Working Party (ADWP) and the Joint Accreditation Committee of EBMT and ISCT (JACIE)
Sharrack, B., Saccardi, R., Alexander, T., Badoglio, M., Burman, J., Farge, D., Greco, R., Jessop, H., Kazmi, M., Kirgizov, K., et al
Bone marrow transplantation. 2019
Abstract
These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials.
-
9.
Innovative strategies minimize engraftment syndrome in multiple myeloma patients with novel induction therapy following autologous hematopoietic stem cell transplantation
Gutierrez-Garcia, G., Rovira, M., Magnano, L., Rosinol, L., Bataller, A., Suarez-Lledo, M., Cibeira, M. T., de Larrea, C. F., Garrote, M., Jorge, S., et al
Bone marrow transplantation. 2018
Abstract
Autologous stem cell transplantation (PBSCT) is standard for young patients in MM and its TRM has decreased after the 2000s. Bortezomib and immunomodulatory agents (IMiDs) in MM have improved the outcome. However, they seem to boost pro-inflammatory stage increasing the incidence of engraftment syndrome (ES). Favorable factors in PBSCT such as G-CSF could increase inflammatory stage during transplant. Corticosteroids have shown an excellent response of ES and some authors propose them as prophylaxis for ES. The aim was to analyze the impact of G-CSF avoidance and corticosteroids' prophylaxis in 170 patients diagnosed of MM treated with bortezomib/IMiDs that underwent PBSCT. We established three groups: Group-I [(G-CSF_administration), 60 patients (35%)], group-II [(nonG-CSF), 60 patients (35%)] and group-III [(nonG-CSF plus corticosteroid's prophylaxis), 50 patients (30%)]. A decreased ES incidence among groups was observed: 62, 42, and 22% (P < 0.0001). The incidence of symptoms mimicking a capillary leak syndrome associated with ES dropped: 43, 32, and 0% (P = 0.03). The G-CSF avoidance and corticosteroids had impact over admission 24, 21, and 20 days (P = 0.001). The most important variables related to ES were HCT-CI >2 (p < 0.0001; HR 8.5) and risk groups (p < 0.0001; HR 7.2). Hence, G-CSF avoidance and corticosteroid's prophylaxis decrease morbidity in patients undergoing PBSCT with MM treated with bortezomib/IMiDs.
-
10.
Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes from the European Society for Blood and Marrow Transplantation
Brierley, C. K., Castilla-Llorente, C., Labopin, M., Badoglio, M., Rovira, M., Ricart, E., Dierickx, D., Vermeire, S., Hasselblatt, P., Finke, J., et al
Journal of Crohn's & colitis. 2018
Abstract
Background/Aims: Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for patients with severe, treatment-refractory Crohn's disease (CD). The evidence base for AHSCT for CD is limited, with one randomised trial (ASTIC) suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe outside the ASTIC trial. Methods: We identified 99 patients in the European Society for Blood and Marrow Transplantation (EBMT) registry who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in 7 countries. Results: Median patient age was 30 years (range 20-65). Patients had failed or been intolerant to a median of 6 lines of drug therapy. 61/82 (74%) had had surgery. Following AHSCT, 53/78 (68%) experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months (range 6-174). 22/82 (27%) required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at last follow-up, 57% (24/42) achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at one year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% CI 1.14-4.83, p=0.02). One patient died due to infectious complications (CMV disease) at day +56. Conclusions: In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted.