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1.
At-Home Foscarnet Administration in Patients with Cytomegalovirus Infection Post-Allogeneic Stem Cell Transplantation: A Unicentric, Safe, and Feasible Program
Ruiz-Boy, S., Pedraza, A., Prat, M., Salas, M. Q., Carcelero, E., Riu-Viladoms, G., Suárez-Lledó, M., Monge-Escartín, I., Rodríguez-Lobato, L. G., Martínez-Roca, A., et al
Pharmaceuticals (Basel, Switzerland). 2023;16(12)
Abstract
Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our hospital designed an at-home FCN administration model to avoid the hospitalization of patients requiring FCN treatment. This study analyzes whether the at-home administration of FCN is as safe and effective as its hospital administration. We collected and compared demographic, clinical, analytical, and economic data of patients with CMV infection post-allo-HCT who received FCN in the hospital (n = 16, 17 episodes) vs. at-home (n = 67, 88 episodes). The proportions of patients with cured CMV infections were comparable between the two groups (65.9% vs. 76.5%, p = 0.395). The median duration of FCN treatment was 15 (interquartile range [IQR] 9-23) and 14 (IQR 11-19) days in the HCU and inpatient cohorts, respectively (p = 0.692). There were no significant differences in the FCN toxicities between groups except for hypocalcemia (26.1% vs. 58.8%, p = 0.007), which was more prevalent in the inpatient cohort. A significant cost-effectiveness was found in the HCU cohort, with a median savings per episode of EUR 5270. It may be concluded that home administration of FCN is a safe, effective, and cost-efficient therapeutic option for patients with CMV infection and disease.
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2.
Easix score correlates with endothelial dysfunction biomarkers and predicts risk of acute graft-versus-host disease after allogeneic transplantation
Pedraza, A., Salas, M. Q., Rodríguez-Lobato, L. G., Escribano-Serrat, S., Suárez-Lledo, M., Martínez-Cebrian, N., Solano, M. T., Arcarons, J., Rosiñol, L., Gutiérrez-García, G., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Plasma biomarkers of endothelial dysfunction have been postulated for the diagnosis and prognosis of acute graft-versus-host disease (aGVHD). However, their use is not validated in clinical practice yet. The endothelial activation and stress index (EASIX), a simple score based on routine laboratory parameters, is considered to be an indirect marker of endothelial damage. High value of EASIX was correlated with worse non-relapse mortality (NRM) and overall survival (OS) and a high risk of sinusoidal obstructive syndrome (SOS) and transplant-associated thrombotic microangiopathy (TA-TMA). OBJECTIVES This study investigates the predictive value of plasma biomarkers and the EASIX score for the prediction of aGVHD. STUDY DESIGN We assessed VCAM-1, TNFR1, and VWF:Ag plasma levels, and EASIX score before allogeneic hematopoietic stem cell transplantation (allo-HSCT), and on days 0, +3, +7, +14, and +21 in an experimental cohort (n=33). EASIX was transformed to a base-2 logarithm to perform the analysis. For the most relevant biomarkers, we estimate the optimal cut-off values and the discriminatory ability to differentiate patients with high-risk of aGVHD. The conclusions obtained in the experimental cohort were validated in a large cohort of 321 patients at the same institution. RESULTS Plasma biomarkers and EASIX showed similar post-transplant dynamics consisting of a progressive increase. Multivariate analysis showed an association between high TNFR1 levels and Log-2 EASIX score on day +7 post-transplant with an increased likelihood of developing aGVHD (HR 1, P=0.002; HR 2.31, P=0.013, respectively). Patients with TNFR1 ≥1300 ng/mL (HR 7.19, P=0.006) and Log2-EASIX ≥3 (HR 14.7, P<0.001) at day +7 post-transplant were more likely to develop aGVHD with high predictive accuracy (C-index of 74% and 81%, respectively). In the validation cohort, patients with Log2-EASIX ≥ 3 on day +7 post-transplant presented a significantly higher incidence of grade II-IV aGVHD (HR 1.94, P=0.004) independent of GVHD prophylaxis (HR 0.38, P=0.004), conditioning regimen (HR 0.59, P=0.02) and type of donor (HR 2.38, P=0.014). CONCLUSIONS Differential degree of endothelial damage can be measured using both EASIX score and plasma biomarkers in the early post-transplant period. Patients at risk of developing aGVHD could be easily identified by a high EASIX score. Both indicators of endothelial activation represent a promising approach to predict aGVHD.
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3.
Impact of measurable residual disease on outcomes of unrelated donor haematopoietic cell transplantation with post-transplant cyclophosphamide in AML in first complete remission
Nagler, A., Labopin, M., Dholaria, B., Blaise, D., Bondarenko, S., Vydra, J., Choi, G., Rovira, M., Reményi, P., Meijer, E., et al
British journal of haematology. 2023
Abstract
Pre-transplant measurable residual disease (MRD) predicts relapse and outcome of allogeneic haematopoietic cell transplantation (allo-HCT). The impact of MRD on the outcomes of post-transplant cyclophosphamide (PTCy)-based allo-HCT from a matched unrelated donor (UD) is unknown. This study assessed the impact of MRD in acute myeloid leukaemia (AML) in the first complete remission (CR1). A total of 272 patients (MRD negative [MRD-], n = 165; MRD positive [MRD+], n = 107) with a median follow-up of 19 (range: 16-24) months were studied. The incidence of grades II-IV and grades III-IV acute GVHD at day 180 was 25.2% and 25% (p = 0.99), and 10.6% and 6.8% (p = 0.29), respectively, and 2-year chronic GVHD was 35% and 30.4% (p = 0.96) in MRD+ and MRD- cohorts, respectively. In multivariate analysis, MRD+ status was associated with a higher incidence of relapse (RI) (hazard ratio [HR] = 2.56, 95% CI: 1.39-4.72), lower leukaemia-free survival (LFS) (HR = 2.04, 95% CI: 1.23-3.39), overall survival (OS) (HR = 1.83, 95% CI: 1.04-3.25) and GVHD-free, relapse-free survival (GRFS) (HR = 1.69, 95% CI: 1.10-2.58). MRD status did not have a significant impact on non-relapse mortality (NRM), or acute or chronic GVHD risk. Among patients with AML undergoing UD allo-HCT with PTCy, pre-transplant MRD+ status predicted a higher relapse rate, lower LFS, OS and GRFS.
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4.
Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) in second complete remission (CR2) transplanted from unrelated donors with post-transplant cyclophosphamide (PTCy). A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Nagler, A., Labopin, M., Swoboda, R., Kulagin, A., Labussière-Wallet, H., Rovira, M., Blaise, D., Vydra, J., Yakoub-Agha, I., Choi, G., et al
Bone marrow transplantation. 2023
Abstract
Post-transplant cyclophosphamide (PTCy) is being increasingly used as graft-versus-host disease (GVHD) prophylaxis post allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) transplanted in first complete remission (CR1). However, results may differ in patients transplanted in CR2. We retrospectively evaluated transplant outcomes of adult AML patients transplanted between 2010-2019 from 9-10/10 human leukocyte antigen (HLA)-matched unrelated donor (UD) in CR2. In total, 127 patients were included (median age 45.5 years, 54% male). Median follow-up was 19.2 months. Conditioning was myeloablative (MAC) in 50.4% and the graft source was peripheral blood in 93.7% of the transplants. Incidence of acute (a)GVHD II-IV and III-IV was 26.2% and 9.2%. Two-year total and extensive chronic (c)GVHD were 34.3% and 13.8 %, respectively. Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were 17.2%, 21.1%, 61.7, %, 65.2%, and 49.3%, respectively. Time from diagnosis to transplant (>18 months) was a favorable prognostic factor for RI, LFS, OS, and GRFS while favorable risk cytogenetics was a positive prognostic factor for OS. The patient's age was a poor prognostic factor for NRM and cGVHD. Finally, the female-to-male combination and reduced intensity conditioning (RIC) were poor and favorable prognostic factors for cGVHD, respectively. We conclude that PTCy is an effective method for GVHD prophylaxis in AML patients undergoing allo-HCT in CR2 from UD.
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5.
Prediction of Nonrelapse Mortality in Patients With Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia Receiving Allogeneic Stem Cell Transplantation With Posttransplantation Cyclophosphamide-based Graft Versus Host Disease Prophylaxis
Hermans, S. J. F., Versluis, J., Labopin, M., Giebel, S., van Norden, Y., Moiseev, I., Blaise, D., Díez Martín, J. L., Meijer, E., Rovira, M., et al
HemaSphere. 2023;7(3):e846
Abstract
Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM-risk scores in patients receiving PTCY-based GVHD prophylaxis, and subsequently developed and validated a novel PTCY-specific NRM-risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY-based GVHD prophylaxis were included. The PTCY-risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation-comorbidity index (HCT-CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2-year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT-CI, and integrated EBMT score was relatively poor for discriminating 2-year NRM (c-statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY-risk score included 10 variables which were collapsed in 3 risk groups estimating 2-year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c-statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c-statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM-risk score for acute leukemia patients receiving PTCY that better predicted 2-year NRM compared with existing models, which might be applicable to the specific toxicities of high-dose cyclophosphamide.
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6.
Endothelial Activation and Stress Index in adults undergoing allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide-based prophylaxis
Escribano-Serrat, S., Rodríguez-Lobato, L. G., Charry, P., Martínez-Cibrian, N., Suárez-Lledó, M., Rivero, A., Moreno-Castaño, A. B., Solano, M. T., Arcarons, J., Nomdedeu, M., et al
Cytotherapy. 2023
Abstract
BACKGROUND AIMS Post-transplant cyclophosphamide (PTCY)-based prophylaxis is becoming widespread for allogeneic hematopoietic cell transplantation (allo-HCT) performed independently of the selected donor source. In parallel, use of the Endothelial Activation and Stress Index (EASIX)-considered a surrogate parameter of endothelial activation-for predicting patient outcomes and clinical complications is gaining popularity in the allo-HCT setting. METHODS We first investigated whether the dynamics of EASIX after allo-HCT differ between patients receiving PTCY and patients receiving other prophylaxis. We then investigated whether the predictive capacity of EASIX persists in PTCY-based allo-HCT. A total of 328 patients transplanted between 2014 and 2020 were included, and 201 (61.2%) received PTCY. RESULTS EASIX trends differed significantly between the groups. Compared with patients receiving other prophylaxis, patients receiving PTCY had lower EASIX on day 0 and higher values between day 7 and day 100. In patients receiving PTCY, higher EASIX correlated significantly with higher non-relapse mortality (NRM) and lower overall survival (OS) when measured before and during the first 180 days after allo-HCT. In addition, higher EASIX scores measured at specific time points were predictors of veno-occlusive disease (VOD), transplant-associated thrombotic microangiopathy (TA-TMA) and grade 2-4 acute graft-versus-host disease (aGVHD) risk. CONCLUSIONS This study demonstrates how EASIX trends vary during the first 180 days after allo-HCT in patients receiving PTCY and those not receiving PTCY and validates the utility of this index for predicting NRM, OS and risk of VOD, TA-TMA and grade 2-4 aGVHD in patients receiving PTCY.
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7.
Post-transplant Cyclophosphamide and Tacrolimus for GVHD Prevention Allo-HCT from HLA-Matched Donors Generates more Advantages than Limitations
Salas, M. Q., Pedraza, A., Charry, P., Suárez-Lledó, M., Rodríguez-Lobato, L. G., Brusosa, M., Solano, M. T., Serrahima, A., Nomdedeu, M., Cid, J., et al
Transplantation and cellular therapy. 2023
Abstract
This study compares the efficacy of PTCY/Tac vs. other prophylaxis in 272 adults undergoing peripheral blood (PB) allo-HCT from HLA-matched donors. 95 (34.9%) adults received PTCY/Tac. Time to neutrophil and platelet engraftment was longer in the PTCY/Tac group (20 vs. 16 days and 19 vs. 12 days). The day +30 cumulative incidence of bacterial bloodstream infection was higher in the PTCY/Tac group (43.2% vs. 13.0%, P<0.001). The cumulative incidences of grade II-IV and III-IV aGVHD at day +180 and of moderate/severe cGVHD at 2 years were 14.7%, 4.2%, and 2.4% for patients receiving PTCY/Tac, and 41.8% (HR 0.29, P<0.001), 15.8%, (HR 0.24, P=0.007) and 47.0% (HR 0.05, P<0.001) for those who did not. Immunosuppression duration was shorter in patients receiving PTCY/Tac (6.2 vs. 9.0 months, P<0.001). PTCY/Tac patients had higher OS (2-years: 74.3 vs. 60.9%, HR 0.54, P=0.012), lower NRM (2-years: 8.6% vs. 15.8%; HR 0.54, P=0.11), comparable CIR (2-years: 26.0% vs. 24.4%, HR 1.03, P=0.89), and higher GRFS (2-years: 59.1% vs. 16.7%; HR 0.32, P<0.001). Using PTCY/Tac in HLA-matched PB allo-HCT improved transplant outcomes at out institution, compared with that of previous prophylaxis, including higher probability of survival in spite of more delayed engraftment and higher bacterial infections.
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8.
Applicability and validation of different prognostic scores in allogeneic hematopoietic cell transplant (HCT) in the post-transplant cyclophosphamide era
Salas, M. Q., Rodríguez-Lobato, L. G., Charry, P., Suárez-Lledó, M., Pedraza, A., Solano, M. T., Arcarons, J., Cid, J., Lozano, M., Rosiñol, L., et al
Hematology, transfusion and cell therapy. 2023
Abstract
We investigated the predictive capacity of six prognostic indices [Karnofsky Performance Status (KPS), Hematopoietic Cell Transplant-Specific Comorbidity Index (HCT-CI), Disease Risk Index (DRI), European Bone Marrow Transplantation (EBMT) and Revised Pre-Transplantation Assessment of Mortality (rPAM) Scores and Endothelial Activation and Stress Index (EASIX)] in 205 adults undergoing post-transplant cyclophosphamide (PTCy)-based allo-HCT. KPS, HCT-CI, DRI and EASIX grouped patients into higher and lower risk strata. KPS and EASIX maintained appropriate discrimination for OS prediction across the first 2 years after allo-HCT [receiver operating characteristic curve (area under the curve (AUC) > 55 %)]. The discriminative capacity of DRI and HCT-CI increased during the post-transplant period, with a peak of prediction at 2 years (AUC of 61.1 % and 61.8 %). The maximum rPAM discriminative capacity was at 1 year (1-year AUC of 58.2 %). The predictive capacity of the EBMT score was not demonstrated. This study validates the discrimination capacity for OS prediction of KPS, HCT-CI, DRI and EASIX in PTCy-based allo-HCT.
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9.
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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10.
Development of an in-house bone marrow collection kit: The Catalan bone marrow transplantation group experience
Fernandez-Sojo, J., Valdivia, E., Esquirol, A., Portos, J. M., Rovira, M., Suarez, M., Diaz-de-Heredia, C., Uría, M. L., Ortí, G., Ferra, C., et al
Vox sanguinis. 2023
Abstract
BACKGROUND AND OBJECTIVES Bone marrow (BM) harvesting is one of the essential sources of stem cells for haematopoietic stem cell transplantation. In 2019, commercial BM collection kits became unavailable in Europe. Consequently, we created an in-house BM collection kit as an alternative. MATERIALS AND METHODS We compared two groups of BM collections. The first collections were taken using an in-house kit from June 2022 through February 2023 and the second with a commercial kit from February 2021 through May 2022. These all took place at seven collection centres (CC). We analysed the harvest quality (cell blood count, CD34+ cells, viability, potency and sterility), the incidents occurring with each kit and the time to neutrophil and platelet engraftment in recipients. RESULTS A total of 23 donors underwent BM harvesting with the in-house kit and 23 with the commercial one. Both cohorts were comparable regarding donor characteristics, CC and time to procedure. No statistical differences were found in harvest quality between the in-house and commercial kits. A new transfusion set was required in three BM harvests (13%) with the in-house kit because of filter clogging. The median time to neutrophil and platelet engraftment was 21 days for both cohorts and 29 days (in-house) and 33 days (commercial), p = 0.284, respectively. CONCLUSION The in-house BM collection kit offers a real approach to solve the diminished supply of commercial kits. A higher risk of filter clogging was observed compared with commercial kits due to the lack of 850 and 500 μm filters.