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A phase 3 randomized, double-blind, comparator-controlled study to evaluate safety, tolerability and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in allogeneic hematopoietic cell transplant recipients (PNEU-STEM)
Wilck, M., Cornely, O. A., Cordonnier, C., Velez, J. D., Ljungman, P., Maertens, J., Selleslag, D., Mullane, K. M., Nabhan, S., Chen, Q., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2023
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Editor's Choice
Abstract
BACKGROUND Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk for pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE™), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. METHODS Participants received 3 doses of V114 or PCV13 in one-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAXTM 23 or a fourth dose of PCV (if they experienced chronic graft versus host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. RESULTS A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90. CONCLUSIONS V114 was well tolerated in allo-HCT recipients with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and higher for V114 serotypes 22F and 33F. Study results support use of V114 in allo-HCT recipients.
PICO Summary
Population
Adults and children who received allo-HCT 90 to 180 days prior to randomization, from 44 centres in 10 countries (n=274)
Intervention
3 doses of V114 pneumococcal conjugate vaccine in one-month intervals starting 3-6 months after transplant. For people who experienced chronic GvHD, a fourth dose of PNEUMOVAXTM 23 was given (n=139)
Comparison
Three doses of PCV13 in pneumococcal conjugate vaccine in one-month intervals starting 3-6 months after transplant. For people who experienced chronic GvHD, a fourth dose was given. (n=135)
Outcome
The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90.
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Defibrotide plus best standard of care compared with best standard of care alone for the prevention of sinusoidal obstruction syndrome (HARMONY): a randomised, multicentre, phase 3 trial
Grupp, S. A., Corbacioglu, S., Kang, H. J., Teshima, T., Khaw, S. L., Locatelli, F., Maertens, J., Stelljes, M., Stepensky, P., Lopez, P., et al
The Lancet. Haematology. 2023
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Editor's Choice
Abstract
BACKGROUND Sinusoidal obstruction syndrome, also known as veno-occlusive disease, is a potentially life-threatening complication of haematopoietic stem-cell transplantation (HSCT). We aimed to compare defibrotide prophylaxis plus best supportive care versus best supportive care alone for sinusoidal obstruction syndrome prevention after HSCT. METHODS This open-label, randomised, multicentre, phase 3 trial was done in 104 centres in 14 countries. Patients who were at least 1 month old, were scheduled to receive allogeneic HSCT (adult [aged >16 years] or paediatric [aged >1 month to ≤16 years] patients) or autologous HSCT (paediatric patients only), and were at high risk or very high risk of developing sinusoidal obstruction syndrome were eligible for inclusion. Patients were randomly assigned (1:1) by an interactive web response system to receive intravenous defibrotide 25 mg/kg per day (four equal doses [6·25 mg/kg per dose]) and best supportive care (determined by individual institutional guidelines; defibrotide prophylaxis group) or best supportive care only (best supportive care group). Randomisation was stratified by sinusoidal obstruction syndrome risk, age, and country. The primary endpoint, sinusoidal obstruction syndrome-free survival at day 30 after HSCT, was assessed by an independent Endpoint Adjudication Committee in the intention-to-treat (ITT) population. Safety was assessed in all patients who received protocol treatment. The trial is registered with ClinicalTrials.gov, NCT02851407. FINDINGS Between Jan 11, 2017, and Oct 20, 2020, 372 patients (172 [46%] women and 200 [54%] men; median age 14·0 years [IQR 4·0-41·0] were randomly assigned to the defibrotide prophylaxis group (n=190) or best supportive care group (n=182; ITT population). On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis, sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the transplantation rather than to study drug. The most common grade 3 or 4 treatment-emergent adverse events were stomatitis (grade 3, 52 [29%] of 181 patients in the defibrotide prophylaxis group and 56 [32%] of 174 patients in the best supportive care group; grade 4, two [1%] in the defibrotide prophylaxis group and two [1%] in the best supportive care group) and febrile neutropaenia (grade 3, 51 [28%] in the defibrotide prophylaxis group and 52 [30%] in the best supportive care group; grade 4, no patients in the defibrotide prophylaxis group and three [2%] in the best supportive care group). Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (sinusoidal obstruction syndrome). INTERPRETATION Defibrotide did not show a benefit in the prophylaxis of sinusoidal obstruction syndrome. Additional studies of carefully selected patients at high risk of sinusoidal obstruction syndrome after HSCT are warranted. FUNDING Jazz Pharmaceuticals.
PICO Summary
Population
Adults and children at least one month old who were scheduled to receive allogeneic transplant or children 1 month – 16 years scheduled to receive autologous transplant, and at high or very high risk of developing sinusoidal obstruction syndrome (n=372)
Intervention
Defibrotide prophylaxis plus best supportive care (n=190)
Comparison
Best supportive care alone (n=182)
Outcome
On the basis of recommendations from the Independent Data Monitoring Committee following completion of the planned interim analysis in the first 280 recruited patients on April 29, 2020, enrolment was prematurely stopped for presumed futility. At the final analysis, sinusoidal obstruction syndrome-free survival by day 30 after HSCT was 67% (95% CI 58-74) in the defibrotide prophylaxis group and 73% (62-80) in the best supportive care group (HR 1·27 [95% CI 0·84-1·93]; p=0·85). Treatment-emergent adverse events were similar between groups during the randomised prophylaxis phase; most treatment-emergent adverse events were related to the transplantation rather than to study drug. Serious treatment-emergent adverse events occurred in 74 (41%) of 181 patients in the defibrotide prophylaxis group and 61 (35%) of 174 patients in the best supportive care group. In the rescue phase, when patients in both treatment groups received defibrotide as rescue treatment, fatal treatment-related adverse events occurred in one (4%) of 25 patients in the defibrotide prophylaxis group (intracranial haemorrhage) and one (3%) of 31 patients in the best supportive care group (sinusoidal obstruction syndrome).
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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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Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS
Michel, C., Robin, M., Morisset, S., Blaise, D., Maertens, J., Chevalier, P., Castilla-Llorente, C., Forcade, E., Ceballos, P., Yakoug-Agha, I., et al
Bone marrow transplantation. 2023;58(5):534-543
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Editor's Choice
Abstract
Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome.
PICO Summary
Population
Patients with higher-risk MDS undergoing allogeneic transplant in centres in France (n=266)
Intervention
HLA-matched sibling donor (MSD, n=79), HLA-matched unrelated donor (MUD, n=139)
Comparison
and HLA haploidentical donor (HID, n=48)
Outcome
The overall survival was significantly different between the three groups with a better OS observed in the MUD group. This observation could be explained by a higher progression-free survival with MUD. The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group. However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]) and a MSD ([sHR]: 0.56 [0.28-1.11]).
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Multipotent mesenchymal stromal cells as treatment for poor graft function after allogeneic hematopoietic cell transplantation: A multicenter prospective analysis
Servais, S., Baron, F., Lechanteur, C., Seidel, L., Baudoux, E., Briquet, A., Selleslag, D., Maertens, J., Poire, X., Schroyens, W., et al
Frontiers in immunology. 2023;14:1106464
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Editor's Choice
Abstract
INTRODUCTION Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT. METHODS We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330). RESULTS Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10(9)/L, Hb > 80g/L and platelet count > 20 x 10(9)/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10(9)/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention. DISCUSSION In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.
PICO Summary
Population
Adults with prolonged severe cytopenia and poor graft function (PGF) after allogeneic transplant in eight centres in Belgium (n=30).
Intervention
Single infusion of third-party donor mesenchymal stromal cells (MSC)
Comparison
None
Outcome
Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 10(9)/L, Hb > 80g/L and platelet count > 20 x 10(9)/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 10(9)/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive.
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Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry
Ljungman, P., Tridello, G., Piñana, J. L., Ciceri, F., Sengeloev, H., Kulagin, A., Mielke, S., Yegin, Z. A., Collin, M., Einardottir, S., et al
Frontiers in immunology. 2023;14:1125824
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Editor's Choice
Abstract
INTRODUCTION COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. METHODS This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic. RESULTS The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022. DISCUSSION Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.
PICO Summary
Population
Adults and children who tested PCR positive to COVID-19 after previous allogeneic transplant, and were reported to the EBMT registry (n=986)
Intervention
Analysis of the outcome of COVID-19 during important phases of the COVID-19.
Comparison
Patients contracting COVID-19 at different time points of the pandemic were compared
Outcome
The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age, worse performance status, contracting COVID-19 within the first 30 days or 30 - 100 days after HCT, ongoing immunosuppression, pre-existing lung disease, and recipient CMV seropositivity had negative impact on overall survival while patients contracting COVID-19 in 2020 or 2021 had worse overall survival than patients with COVID-19 diagnosed in 2022.
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Impact of donor-derived CD34?+?infused cell dose on outcomes of patients undergoing allo-HCT following reduced intensity regimen for myelofibrosis: a study from the Chronic Malignancies Working Party of the EBMT
Czerw, T., Iacobelli, S., Malpassuti, V., Koster, L., Kröger, N., Robin, M., Maertens, J., Chevallier, P., Watz, E., Poiré, X., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
The optimal CD34?+?cell dose in the setting of RIC allo-HCT for myelofibrosis (MF) remains unknown. We retrospectively analyzed 657 patients with primary or secondary MF transplanted with use of peripheral blood (PB) stem cells after fludarabine/melphalan or fludarabine/busulfan RIC regimen. Median patient age was 58 (range, 22-76) years. Donors were HLA-identical sibling (MSD) or unrelated (UD). Median follow-up was 46 (2-194) months. Patients transplanted with higher doses of CD34?+?cells (>7.0?×?10(6)/kg), had an increased chance of achievement of both neutrophil (hazard ratio (HR), 1.46; P?0.001) and platelet engraftment (HR, 1.43; P?0.001). In a model with interaction, for patients transplanted from a MSD, higher CD34?+?dose was associated with improved overall survival (HR, 0.63; P?=?0.04) and relapse-free survival (HR, 0.61; P?=?0.02), lower risk of non-relapse mortality (HR, 0.57; P?=?0.04) and higher rate of platelet engraftment. The combined effect of higher cell dose and UD was apparent only for higher neutrophil and platelet recovery rate. We did not document any detrimental effect of high CD34?+?dose on transplant outcomes. More bulky splenomegaly was an adverse factor for survival, engraftment and NRM. Our analysis suggests a potential benefit for MF patients undergoing RIC PB-allo-HCT receiving more than 7.0?×?10(6)/kg CD34?+?cells.
PICO Summary
Population
Patients with primary or secondary myelofibrosis (MF, n=657)
Intervention
Peripheral blood (PB) stem cells transplantation, after fludarabine/melphalan or fludarabine/busulfan with a reduced intensity conditioning (RIC) regimen.
Comparison
None
Outcome
Median patient age was 58 (range, 22-76) years. Donors were HLA-identical sibling (MSD) or unrelated (UD). Median follow-up was 46 (2-194) months. Patients transplanted with higher doses of CD34+ cells (>7.0 ×10(6)/kg), had an increased chance of achievement of both neutrophil (hazard ratio (HR), 1.46) and platelet engraftment (HR, 1.43). In a model with interaction, for patients transplanted from a MSD, higher CD34+ dose was associated with improved overall survival (HR, 0.63) and relapse-free survival (HR, 0.61), lower risk of non-relapse mortality (HR, 0.57) and higher rate of platelet engraftment. The combined effect of higher cell dose and UD was apparent only for higher neutrophil and platelet recovery rate. We did not document any detrimental effect of high CD34+ dose on transplant outcomes. More bulky splenomegaly was an adverse factor for survival, engraftment and NRM.
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Comparison of mycophenolate mofetil and calcineurin inhibitor versus calcineurin inhibitor-based graft-versus-host-disease prophylaxis for matched unrelated donor transplant in acute myeloid leukemia. A study from the ALWP of the EBMT
Paviglianiti, A., Labopin, M., Blaise, D., Socié, G., Bulabois, C. E., Lioure, B., Ceballos, P., Blau, I. W., Guillerm, G., Maertens, J., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
The association of Cyclosporine A (CsA) and mycophenolate mofetil (MMF) has increased in the setting of reduced intensity conditioning (RIC). Nevertheless, the use of CsA or CsA+MMF has not been reported in a large and uniform cohort. We analyzed 497 patients with acute myeloid leukemia in complete remission (CR) who underwent matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). All patients received a fludarabine busulfan RIC regimen and anti-thymocyte globulin (ATG) with either CsA alone or in combination with MMF. The cumulative incidence (CI) of grade II-IV acute GvHD was 27% (95% CI 21-33%) for CsA and 33% (95% CI 27-38%) for CsA+MMF (p?=?0.25). The 2-year CI of chronic GvHD was 38% (95% CI 31-45%) and 33% (95% CI 28-39%) for the CsA and the CsA+MMF group, respectively (p?=?0.26). On multivariate analysis, no statistically significant differences with respect to relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), acute and chronic GvHD were found between the two groups, also when conducting a subgroup analysis in peripheral blood stem cells (PBSC) recipients. Our results support the importance of randomized trial to identify patients who could benefit from the addition of MMF in MUD HSCT.
PICO Summary
Population
Patients who underwent a 10/10 MUD HSCT for acute myeloid leukaemia (n=497)
Intervention
Cyclosporine A and mycophenolate mofetil (CsA + MMF, n=314)
Comparison
Cyclosporine A alone (CsA, n=183)
Outcome
The cumulative incidence (CI) of grade II-IV acute GvHD was 27% for CsA and 33% for CsA+MMF. The 2-year CI of chronic GvHD was 38% and 33% for the CsA and the CsA+MMF group, respectively. On multivariate analysis, no statistically significant differences with respect to relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), acute and chronic GvHD were found between the two groups, also when conducting a subgroup analysis in peripheral blood stem cells (PBSC) recipients.
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Comparison of DIPSS and MYSEC-PM for prediction of outcome in post-PV and ET myelofibrosis after allogeneic stem-cell transplantation
Gagelmann, N., Eikema, D. J., de Wreede, L. C., Koster, L., Wolschke, C., Arnold, R., Kanz, L., McQuaker, G., Marchand, T., Socie, G., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC- PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C >0.5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (34-54 months) being different in post-PV (45 months) and post-ET myelofibrosis (38 months). Survival at one, two, and four years was 70% (63-77%), 61% (53- 69%) and 52% (43-61%) for the total cohort, 70% (59-80%), 61% (49-73%) and 51% (38-64%) for post-PV, and 71% (61-81%), 61% (50-72%) and 54% (42-66%) for post-ET myelofibrosis (p=0.78). Overall, the DIPSS was not significantly predictive of outcome (p=0.28). With respect to the MYSEC-PM, overall survival at four years was 69% for the low-risk, 55% for the intermediate-1-risk, 47% for the intermediate-2-risk, and 22% (0-45%) for the high-risk group. The prognostic model was predictive of survival overall (p=0.05) while groups with intermediate-2 and high risk showed no significant difference (p=0.44). Assessment of prognostic utility yielded C-index of 0.575 (0.502-0.648) for the DIPSS while assessment of the MYSEC-PM resulted in C-statistics of 0.636 (0.563-0.708) indicating improvement in prediction of posttransplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (p=0.04) and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (p=0.01) showed worse survival. In conclusion, incorporating transplant-specific as well as clinical and mutational information together with the MYSEC-PM may enhance risk stratification.
PICO Summary
Population
Patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. (n=159)
Intervention
MYelofibrosis SECondary to PV and ET prognostic model (MYSEC- PM)
Comparison
Dynamic International Prognostic Scoring System (DIPSS)
Outcome
Overall, the DIPSS was not significantly predictive of outcome. MYSEC-PM was predictive of survival overall, while groups with intermediate-2 and high risk showed no significant difference. Assessment of prognostic utility yielded C-index of 0.575 for the DIPSS while assessment of the MYSEC-PM resulted in C-statistics of 0.636, indicating improvement in prediction of posttransplant survival using the new MYSEC-PM.
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Tandem autologous stem cell transplantation improves outcome in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the Chronic Malignancies Working Party of EBMT
Gagelmann, N., Eikema, D. J., Koster, L., Caillot, D., Pioltelli, P., Lleonart, J. B., Remenyi, P., Blaise, D., Schaap, N., Trneny, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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Editor's Choice
Abstract
Although high-dose therapy and autologous stem cell transplantation combined with novel agents is still the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease and high-risk cytogenetics is not defined yet. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with extramedullary disease undergoing single autologous (n=373), tandem autologous (n=84), or autologous-allogeneic transplantation (n=31) between 2003 and 2015. At least one high-risk abnormality was present in 41% (n=202), with del(17p) (40%) and t(4;14) (45%) being the most frequent. More than one high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival and progression-free survival of 54% and 29% vs. 78% and 49% for standard-risk (p<0.001, respectively). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, overall and progression-free survival were 70% and 43% for single autologous vs. 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic (p=0.06 and p=0.30). In multivariate analysis, high-risk cytogenetics were associated with worse survival (HR, 2.00; p=0.003) while tandem autologous significantly improved outcome vs. single autologous transplant (hazard ratios, 0.46 and 0.64; p=0.02 and p=0.03). Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival while results were limited due to small population (hazard ratio, 0.31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with extramedullary disease and significantly worsens outcome after single autologous while tandem autologous transplant strategy may overcome onset poor prognosis.
PICO Summary
Population
Adult myeloma patients with extramedullary disease (n=488).
Intervention
Tandem autologous transplantation (n=84) or autologous-allogeneic transplantation (n=31)
Comparison
Single autologous transplantation (n=373)
Outcome
Overall and progression-free survival were 70% and 43% for single autologous vs. 83% and 52% for tandem autologous and 88% and 58% for autologous-allogeneic. In multivariate analysis, high-risk cytogenetics were associated with worse survival, while tandem autologous significantly improved outcome vs. single autologous transplant. Autologous-allogeneic transplant did not significantly differ in outcome but appeared to improve survival while results were limited due to small population.