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1.
Impact of comorbidities and body mass index on the outcomes of allogeneic hematopoietic cell transplantation in myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of EBMT
Polverelli, N., Bonneville, E. F., de Wreede, L. C., Koster, L., Kröger, N. M., Schroeder, T., Peffault de Latour, R., Passweg, J., Sockel, K., Broers, A. E. C., et al
American journal of hematology. 2024
Abstract
Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT.
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Allogeneic hematopoietic cell transplantation in older myelofibrosis patients: a study of the Chronic Malignancies Working Party of EBMT and the Spanish Myelofibrosis Registry
Hernández-Boluda, J. C., Pereira, A., Kröger, N., Cornelissen, J. J., Finke, J., Beelen, D., de Witte, M., Wilson, K., Platzbecker, U., Sengeloev, H., et al
American journal of hematology. 2021
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is increasingly used in older myelofibrosis (MF) patients, but its risk/benefit ratio compared to non-transplant approaches has not been evaluated in this population. We analyzed the outcomes of allo-HCT in 556 MF patients aged > 65?years from the EBMT registry, and determined the excess mortality over the matched general population of MF patients > 65?years managed with allo-HCT (n=556) or conventional drug treatment (n=176). The non-transplant cohort included patients with intermediate-2 or high risk DIPSS from the Spanish Myelofibrosis Registry. After a median follow-up of 3.4?years, the estimated 5-year survival rate, non-relapse mortality (NRM), and relapse incidence after transplantation was 40%, 37%, and 25%, respectively. Busulfan-based conditioning was associated with decreased mortality (HR: 0.7, 95% CI: 0.5-0.9) whereas the recipient CMV+/donor CMV- combination (HR: 1.7, 95% CI: 1.2-2.4) and the JAK2 mutated genotype (HR: 1.9, 95% CI: 1.1-3.5) predicted higher mortality. Busulfan-based conditioning correlated with improved survival due to less NRM, despite its higher relapse rate when compared with melphalan-based regimens. Excess mortality was higher in transplanted patients than in the non-HCT cohort in the first year of follow-up (ratio: 1.93, 95% CI: 1.13-2.80), whereas the opposite occurred between the 4th and 8th follow-up years (ratio: 0.31, 95% CI: 0.18-0.53). Comparing the excess mortality of the two treatments, male patients seemed to benefit more than females from allo-HCT, mainly due to their worse prognosis with non-transplant approaches. These findings could potentially enhance counseling and treatment decision-making in elderly transplant-eligible MF patients. This article is protected by copyright. All rights reserved.
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3.
Thiotepa-busulfan-fludarabine (TBF) conditioning regimen in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis: an outcome analysis from the Chronic Malignancies Working Party of the EBMT
Battipaglia, G., Mauff, K., Wendel, L., Angelucci, E., Mohty, M., Arcese, W., Santarone, S., Rubio, M. T., Kroger, N., Fox, M. L., et al
Bone marrow transplantation. 2021
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in MF. There is no consensus on the optimal conditioning regimen. We report outcomes of 187 patients with MF transplanted between 2010 and 2017 conditioned with TBF. Median age was 58 years. Median interval from diagnosis to allo-HCT was 44 months. Donors were haploidentical (41%), unrelated (36%) or HLA-identical siblings (23%). Stem cell source was PB in 60%. Conditioning was myeloablative in 48% of cases. Antithymocyte globulin (ATG) was used in 41% of patients. At 100 days, neutrophil and platelet engraftment were 91% and 63% after a median of 21 and 34 days, respectively. Grade II-IV and III-IV acute GVHD occurred in 24% and 12%, while at 3 years, all grade chronic GVHD and chronic extensive GVHD had been diagnosed in 38% and 11%. At 3 years, OS, RFS and GRFS were 55%, 49% and 43%, respectively. RI and NRM were 17% and 33%. On multivariate analysis, poor KPS and the use of unrelated donors were associated with worse GRFS and a higher grade II-IV acute GVHD, respectively. Neither donor type nor intensity of the conditioning regimen influenced survival outcomes. TBF is a feasible conditioning regimen in allo-HCT for MF in all donor settings although longer term outcomes are required.
PICO Summary
Population
Patients with myelofibrosis (MF, n=187)
Intervention
Thiotepa-busulfan-fludarabine (TBF) conditioning regimen and allogeneic transplant
Comparison
None
Outcome
At 100 days, neutrophil and platelet engraftment were 91% and 63% after a median of 21 and 34 days, respectively. Grade II-IV and III-IV acute GVHD occurred in 24% and 12%, while at 3 years, all grade chronic GVHD and chronic extensive GVHD had been diagnosed in 38% and 11%. At 3 years, OS, RFS and GRFS were 55%, 49% and 43%, respectively. RI and NRM were 17% and 33%. On multivariate analysis, poor KPS and the use of unrelated donors were associated with worse GRFS and a higher grade II-IV acute GVHD, respectively. Neither donor type nor intensity of the conditioning regimen influenced survival outcomes.
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4.
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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5.
Splenectomy before allogeneic hematopoietic cell transplantation for myelofibrosis: a French nationwide study
Bossard, J. B., Beuscart, J. B., Robin, M., Mohty, M., Barraco, F., Chevallier, P., Marchand, T., Rubio, M. T., Charbonnier, A., Blaise, D., et al
American journal of hematology. 2020
Abstract
The value of pretransplant splenectomy in patients with myelofibrosis (MF) is subject to debate, since the procedure may preclude subsequent allogeneic hematopoietic cell transplantation (allo-HCT). To determine the impact of pretransplant splenectomy on the incidence of allo-HCT, we conducted a comprehensive retrospective study of all patients with MF for whom an unrelated donor search had been initiated via the French bone marrow transplantation registry (RFGM) between January 1(st) , 2008, and January 1(st) , 2017. Additional data were collected from the patients' medical files and a database held by the French-Language Society for Bone Marrow Transplantation and Cell Therapy (SFGM-TC). We used a multistate model with four states ("RFGM registration"; "Splenectomy"; "Death before allo-HCT", and "Allo-HCT") to evaluate the association between splenectomy and the incidence of allo-HCT. The study included 530 patients from 57 centers. With a median follow-up time of 6 years, we observed 81 splenectomies, 99 deaths before allo-HCT (90 without splenectomy and 9 after), and 333 allo-HCTs (268 without splenectomy and 65 after). In a bivariable analysis, the hazard ratio [95% confidence interval (CI)] for the association of splenectomy with allo-HCT was 7.2 [5.1-10.3] in the first 4 months and 1.18 [0.69-2.03] thereafter. The hazard ratio [95%CI] for death associated with splenectomy was 1.58 [0.79-3.14]. These reassuring results suggest that splenectomy does not preclude allo-HCT in patients with MF. This article is protected by copyright. All rights reserved.
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6.
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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Free full text
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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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7.
Antilymphocyte Globulin for matched sibling donor transplantation in patients with myelofibrosis
Robin, M., Chevret, S., Koster, L., Wolschke, C., Yakoub-Agha, I., Bourhis, J. H., Chevallier, P., Cornelissen, J. J., Remenyi, P., Maertens, J., et al
Haematologica. 2019
Abstract
Antihuman T-lymphocyte immunoglobulin is still much debated in the setting of transplant from an HLA matched related donor. Acute and chronic graft-versus-host disease are the main cause of morbidity and mortality after allogeneic hematopoietic stem cell in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis. 287 patients were included in the study. Cumulative incidence of grade 2-4 acute graft-versus-host disease was 26% and 41% with or without antihuman T-lymphocyte immunoglobulin. Chronic graft-versus-host disease incidence was 52% and 55%. Non-adjusted overall Survival, Disease Free Survival and non-relapse mortality were 55% vs 53%, 49% vs 45%, and 32% vs 31%, respectively with or without antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that acute graft-versus-host disease risk was lower following antihuman T-lymphocyte immunoglobulin (Hazard ratio : 0.54, p=0.010) whilst it did not decrease the risk of chronic graft-versus-host disease. Hazard ratio for overall survival and non-relapse mortality were 0.66 and 0.64, with p-value at 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease and relapse free survival and relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases acute graft-versus-host disease risk without increasing relapse risk.
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8.
Family mismatched allogeneic stem cell transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of EBMT
Raj, K., Eikema, D. J., McLornan, D. P., Olavarria, E., Blok, H. J., Bregante, S., Ciceri, F., Passweg, J., Ljungman, P., Schaap, N., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
This analysis includes 56 Myelofibrosis (MF) patients transplanted from family mismatched donor between 2009-2015 enrolled in the European Society for Blood and Marrow Transplantation (EBMT) database. The median age was 57 years (range, 38-72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34+ cell dose was 4.8x10(6)/kg (1.7-22.9x10(6)/kg) (n=43). Conditioning was predominantly myeloablative (MAC) in 70% and reduced intensity (RIC) in the remainder. Regimens were heterogeneous with Thiotepa, Busulphan Fludarabine (TBF) and post-transplant cyclophosphamide (PTCy) used in 59%. The incidence of neutrophil engraftment by 28 days was 82% (range, 70-93%), at a median of 21 days (range,19-23). At 2 yrs. the CI of primary Graft failure was 9% (1-16%) and secondary graft failure was 13% (4-22%).The cumulative incidence (CI) of grades II-IV acute GvHD (aGvHD) and III-IV was 28% (16-40%) and 9% (2-17%) at 100 days. The CI of chronic GvHD (cGvHD) at 1 year was 45% (32-58%) but CI of death without cGVHD by 1 year was 20% (10-31%). With a median follow up of 32 months, the 1- and 2-year OS was 61% (48-74%) and 56% (41-70%) respectively. The 1- and 2- year PFS was 58% (45-71%) and 43% (28-58%) with a 2-year CI of relapse of 19% (7-31%). The 2-year non-relapse mortality (NRM) was 38% (24-51%). This retrospective study of MF allo-SCT utilising family mismatched donors, demonstrates feasibility of the approach, timely neutrophil engraftment in over 80% of cases and acceptable OS and PFS rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimise the risk of graft failure and the relatively high NRM need to be employed, ideally in a multicentre prospective fashion.