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1.
Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis
Gagelmann, N., Hobbs, G. S., Campodonico, E., Helbig, G., Novak, P., Schroeder, T., Schneider, A., Rautenberg, C., Reinhardt, H. C., Bosques, L., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.
PICO Summary
Population
Adults with with primary myelofibrosis, post polycythemia vera, and post-essential thrombocythemia myelofibrosis, identified from centres worldwide (n=171)
Intervention
Splenic irradiation within a median of 2 weeks before transplant (n=59)
Comparison
Matched controls receiving immediate transplant without splenic irradiation (n=56), or who had splenectomy (n=56)
Outcome
Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse, showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy.
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2.
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 patients with CALR-mutated myelofibrosis: a study of the Chronic Malignancies Working Party of EBMT
Hernández-Boluda, J. C., Eikema, D. J., Koster, L., Kröger, N., Robin, M., de Witte, M., Finke, J., Finazzi, M. C., Broers, A., Raida, L., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for myelofibrosis (MF) but assessing risk-benefit in individual patients is challenging. This complexity is amplified in CALR-mutated MF patients, as they live longer with conventional treatments compared to other molecular subtypes. We analyzed outcomes of 346 CALR-mutated MF patients who underwent allo-HCT in 123 EBMT centers between 2005 and 2019. After a median follow-up of 40 months, the estimated overall survival (OS) rates at 1, 3, and 5 years were 81%, 71%, and 63%, respectively. Patients receiving busulfan-containing regimens achieved a 5-year OS rate of 71%. Non-relapse mortality (NRM) at 1, 3, and 5 years was 16%, 22%, and 26%, respectively, while the incidence of relapse/progression was 11%, 15%, and 17%, respectively. Multivariate analysis showed that older age correlated with worse OS, while primary MF and HLA mismatched transplants had a near-to-significant trend to decreased OS. Comparative analysis between CALR- and JAK2-mutated MF patients adjusting for confounding factors revealed better OS, lower NRM, lower relapse, and improved graft-versus-host disease-free and relapse-free survival (GRFS) in CALR-mutated patients. These findings confirm the improved prognosis associated with CALR mutation in allo-HCT and support molecular profiling in prognostic scoring systems to predict OS after transplantation in MF.
PICO Summary
Population
Adults with CALR-mutated myelofibrosis from centres in Europe (n=346)
Intervention
First allogeneic transplant at an EBMT centre between 2005 and 2019
Comparison
None
Outcome
After a median follow-up of 40 months, the estimated overall survival (OS) rates at 1, 3, and 5 years were 81%, 71%, and 63%, respectively. Patients receiving busulfan-containing regimens achieved a 5-year OS rate of 71%. Non-relapse mortality (NRM) at 1, 3, and 5 years was 16%, 22%, and 26%, respectively, while the incidence of relapse/progression was 11%, 15%, and 17%, respectively. Multivariate analysis showed that older age correlated with worse OS, while primary MF and HLA mismatched transplants had a near-to-significant trend to decreased OS. Comparative analysis between CALR- and JAK2-mutated MF patients adjusting for confounding factors revealed better OS, lower NRM, lower relapse, and improved graft-versus-host disease-free and relapse-free survival (GRFS) in CALR-mutated patients.
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Outcomes after Allogeneic Hematopoietic Cell Transplant in patients diagnosed with Blast Phase of Myeloproliferative Neoplasms: a retrospective study from the Chronic Malignancies Working Party of the EBMT
Ortí, G., Gras, L., Zinger, N., Finazzi, M. C., Sockel, K., Robin, M., Forcade, E., Avenoso, D., Kröger, N., Finke, J., et al
American journal of hematology. 2023
Abstract
Allogeneic haematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm (BP-MPN). We report on a large, retrospective EBMT registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005-2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year OS was 36% (95% CI, 32-36). Factors associated with lower OS were Karnofsky Performance Status (KPS) <90 (HR 1.65, p<0.001) and active disease at allo-HCT (HR 1.45, p<0.001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p=0.008). In a selected patients population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS<90 (HR 1.4, p=0.001) and active disease (HR 1.44, p=0.0004) were associated with a lower PFS. Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p=0.008). Active disease at allo-HCT (HR 1.34, p=0.03) was associated with a higher cumulative incidence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p=0.02) associated with a lower RI. Lastly, KPS<90 (HR 1.91, p<0.001), active disease (HR 1.74, p=0.003) and allo-HCT from mismatched related donors were associated with a higher NRM (HR 2.66, p=0.003). In this large series of BP-MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS≥90 and in CR at transplant had a better prognosis. This article is protected by copyright. All rights reserved.
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Posttransplant cyclophosphamide versus antithymocyte globulin in patients with acute lymphoblastic leukemia treated with allogeneic hematopoietic cell transplantation from matched unrelated donors. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Giebel, S., Labopin, M., Salmenniemi, U., Socié, G., Bondarenko, S., Blaise, D., Kröger, N., Vydra, J., Grassi, A., Bonifazi, F., et al
Cancer. 2023
Abstract
BACKGROUND The aim of this study was to compare two immunosuppressive strategies, based on the use of either rabbit antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY), as a prophylaxis of graft-versus-host disease (GVHD) for patients with acute lymphoblastic leukemia (ALL) in first complete remission who underwent hematopoietic cells transplantation from matched unrelated donors. METHODS Overall, 117 and 779 adult patients who received PTCY and ATG, respectively, between the years 2015 and 2020 were included in this retrospective study. The median patient age was 40 and 43 years in the PTCY and ATG groups, respectively, and 37% and 35% of patients, respectively, had Philadelphia chromosome-positive ALL. RESULTS In univariate analysis, the cumulative incidence of acute and chronic GVHD did not differ significantly between the study groups. The cumulative incidence of relapse at 2 years was reduced in the PTCY group (18% vs. 25%; p = .046) without a significant impact on nonrelapse mortality (11% vs. 16% in the ATG group; p = .29). The rates of leukemia-free survival (LFS) and overall survival were 71% versus 59%, respectively (p = .01), and 82% versus 74%, respectively (p = .08). In multivariate analysis, the receipt of ATG compared with PTCY was associated with a reduced risk of extensive chronic GVHD (hazard ratio, 0.54; 95% confidence interval, 0.3-0.98; p = .04) and an increased risk of low LFS (hazard ratio, 1.57; 95% confidence interval, 1.01-2.45; p = .045). CONCLUSIONS The receipt of ATG compared with PTCY, despite the reduced risk of extensive chronic GVHD, is associated with inferior LFS in adults with ALL who undergo hematopoietic cell transplantation from 10/10 human leukocyte antigen-matched unrelated donors. These findings warrant verification in prospective trials.
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6.
A Simple Prognostic System in Myelofibrosis Patients Undergoing Allogeneic Stem Cell Transplant: A CIBMTR/EBMT analysis
Tamari, R., McLornan, D. P., Ahn, K. W., Estrada-Merly, N., Hernandez-Boluda, J. C., Giralt, S. A., Palmer, J. M., Gale, R. P., DeFilipp, Z., Marks, D., et al
Blood advances. 2023
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Free full text
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Full text
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Editor's Choice
Abstract
To develop a prognostic model for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) for myelofibrosis (MF). We examined 623 patients undergoing allo-HCT between 2000 - 2016 in the USA (CIBMTR cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients transplanted in Europe (EBMT cohort) (n = 623). Age above 50 (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98 -1.96), and HLA matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with increased hazard of death and were assigned 1 point. Hemoglobin lower than 100g/L at time of transplant (HR, 1.63; 95% CI, 1.2- 2.19), and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25- 2.52), were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points) and high score (5 points) were 69% (95% CI, 61% -76 %), 51 % (95% CI, 46% -56.4 %), and 34% (95% CI, 21% - 49%), respectively (P. < 0.001). Increasing score was predictive of increased transplant related mortality (TRM) (P .0017) but not for relapse (P. 0.12). The derived score was predictive for OS (P. < 0.001) and TRM (P. 0.002) but not relapse (P. 17) in the EBMT cohort as well. The proposed system was prognostic of survival in two large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF on transplant outcomes.
PICO Summary
Population
Adults aged 40 or over undergoing allogeneic transplantation for myelofibrosis and reported to the CIBMTR or EBMT registries (n=1246)
Intervention
Cox regression model of prognostic factors developed with patients from the CIBMTR registry (n=623)
Comparison
Validation of the model using a cohort from the EBMT registry (n=623)
Outcome
Age above 50 (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98 -1.96), and HLA matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with increased hazard of death and were assigned 1 point. Hemoglobin lower than 100g/L at time of transplant (HR, 1.63; 95% CI, 1.2- 2.19), and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25- 2.52), were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points) and high score (5 points) were 69% (95% CI, 61% -76 %), 51 % (95% CI, 46% -56.4 %), and 34% (95% CI, 21% - 49%), respectively. Increasing score was predictive of increased transplant related mortality (TRM) but not for relapse. The derived score was predictive for OS and TRM but not relapse in the EBMT cohort as well.
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Early liver complications after allogeneic haematopoietic stem cell transplantation in patients with myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of the EBMT
Robin, M., Gras, L., Koster, L., Gagelmann, N., van Gorkom, G., Ederr, M., Itälä-Remes, M., Zuckerman, T., Beguin, Y., Schaap, N., et al
British journal of haematology. 2023
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Splenomegaly in patients with primary or secondary myelofibrosis who are candidates for allogeneic hematopoietic cell transplantation: a Position Paper on behalf of the Chronic Malignancies Working Party of the EBMT
Polverelli, N., Hernández-Boluda, J. C., Czerw, T., Barbui, T., D'Adda, M., Deeg, H. J., Ditschkowski, M., Harrison, C., Kröger, N. M., Mesa, R., et al
The Lancet. Haematology. 2022
Abstract
Splenomegaly is a hallmark of myelofibrosis, a debilitating haematological malignancy for which the only curative option is allogeneic haematopoietic cell transplantation (HCT). Considerable splenic enlargement might be associated with a higher risk of delayed engraftment and graft failure, increased non-relapse mortality, and worse overall survival after HCT as compared with patients without significantly enlarged splenomegaly. Currently, there are no standardised guidelines to assist transplantation physicians in deciding optimal management of splenomegaly before HCT. Therefore, the aim of this Position Paper is to offer a shared position statement on this issue. An international group of haematologists, transplantation physicians, gastroenterologists, surgeons, radiotherapists, and radiologists with experience in the treatment of myelofibrosis contributed to this Position Paper. The key issues addressed by this group included the assessment, prevalence, and clinical significance of splenomegaly, and the need for a therapeutic intervention before HCT for the control of splenomegaly. Specific scenarios, including splanchnic vein thrombosis and COVID-19, are also discussed. All patients with myelofibrosis must have their spleen size assessed before allogeneic HCT. Myelofibrosis patients with splenomegaly measuring 5 cm and larger, particularly when exceeding 15 cm below the left costal margin, or with splenomegaly-related symptoms, could benefit from treatment with the aim of reducing the spleen size before HCT. In the absence of, or loss of, response, patients with increasing spleen size should be evaluated for second-line options, depending on availability, patient fitness, and centre experience. Splanchnic vein thrombosis is not an absolute contraindication for HCT, but a multidisciplinary approach is warranted. Finally, prevention and treatment of COVID-19 should adhere to standard recommendations for immunocompromised patients.
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Outcome of allogeneic haematopoietic cell transplantation in eosinophilic disorders: A retrospective study by the chronic malignancies working party of the EBMT
McLornan, D. P., Gras, L., Martin, I., Sirait, T., Schroeder, T., Blau, I. W., Kuball, J., Byrne, J., Collin, M., Stadler, M., et al
British journal of haematology. 2022
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10.
Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European Society for Blood and Marrow Transplantation (EBMT)
Polverelli, N., Mauff, K., Kröger, N., Robin, M., Beelen, D., Beauvais, D., Chevallier, P., Mohty, M., Passweg, J., Rubio, M. T., et al
American Journal of Hematology. 2021;96(1):69-79
Abstract
The role of spleen size and splenectomy for the prediction of post-allogeneic hematopoietic stem cell transplant (allo-HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000-2017 after either fludarabine-busulfan or fludarabine-melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000-2009 vs 14.1% in 2010-2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44-0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01-2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67-1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length ≥ 15 cm (HR 0.44, 95% CI 0.28-0.69, P < .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14-0.49, P < .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87-2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.