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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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Graft-versus-host disease and impact on relapse in myelofibrosis undergoing hematopoietic stem cell transplantation
Oechsler, S., Gagelmann, N., Wolschke, C., Janson, D., Badbaran, A., Klyuchnikov, E., Massoud, R., Rathje, K., Richter, J., Schäfersküpper, M., et al
Bone marrow transplantation. 2024
Abstract
Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the only curative treatment for myelofibrosis (MF). Relapse occurs in 10-30% and remains a major factor for dismal outcomes. Previous work suggested that graft-versus-host disease (GVHD) might be associated with risk of relapse. This study included 341 patients undergoing their first (n = 308) or second (n = 33) alloHSCT. Anti-T-lymphocyte or antithymocyte globulin was used for GVHD prophylaxis in almost all patients. Median time to neutrophile and platelet engraftment was 13 days and 19 days, respectively. The cumulative incidence of acute GVHD grade II-IV was 41% (median, 31 days; range, 7-112). Grade III-IV acute GVHD was observed in 22%. The cumulative incidence of chronic GVHD was 61%. Liver was affected in 23% of acute GVHD cases and 46% of chronic GVHD cases. Severe acute GVHD was associated with high non-relapse mortality. The development of acute GVHD grade II and moderate GVHD was an independent factor for reduced risk for relapse after transplantation without increased risk for non-relapse mortality, while especially acute GVHD grade IV was associated with high non-relapse mortality. Last, we identified that ongoing response to ruxolitinib, accelerated-phase MF at time of transplantation and splenectomy prior to transplantation were independent predictors for relapse.
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Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation
Gagelmann, N., Badbaran, A., Salit, R. B., Schroeder, T., Gurnari, C., Pagliuca, S., Panagiota, V., Rautenberg, C., Cassinat, B., Thol, F. R., et al
Blood. 2023
Abstract
TP53 mutations (TP53MT) have been associated with poor outcomes in various hematologic malignancies, but no data exist on its role in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HSCT). Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53MTin this setting. Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 30 showed a multi-hit configuration. Median variant allele frequency was 20.3%. Cytogenetic risk was favorable (71%), unfavorable (23%), and very high (6%), with complex karyotype present in 36 patients (10%). Median survival of TP53MT patients was 1.5 years vs 13.5 years for the TP53WT group (P<0.001). Outcome was driven by multi-hit TP53MT constellation (P<0.001), showing 6-year survival of 56% for single-hit vs 25% for multi-hit TP53MT carriers vs 64% for TP53WT. Outcome was independent of current transplant-specific risk factors and conditioning intensity. Similarly, cumulative incidence of relapse was 17% for single-hit vs 52% for multi-hit vs 21% for TP53WT. Ten patients with TP53MT (20%) presented as leukemic transformation vs only 7 (2%) in the TP53WT group (P<0.001). Out of the 10 patients with TP53MT, 8 showed multi-hit constellation. Median time to leukemic transformation was shorter for multi-and single-hit TP53MT (0.7 and 0.5 years, respectively) vs 2.5 years for TP53WT. In summary, multi-hit TP53MT represents a very high-risk group in myelofibrosis patients undergoing HSCT, whereas single-hit TP53MTalone showed similar outcome to non-mutated patients, informing prognostication for survival and relapse together with current transplant-specific tools.
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5.
JAK2V617F Mutation and Associated Chromosomal Alterations in Primary and Secondary Myelofibrosis and Post-HCT Outcomes
Rafati, M., Brown, D., Zhou, W., Jones, K. M., Luo, W., St Martin, A., Wang, Y., He, M., Spellman, S. R., Wang, T., et al
Blood advances. 2023
Abstract
JAK2V617F is the most common driver mutation in primary or secondary myelofibrosis in which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting is limited. We identified all patients with MF who received HCT between 2000 and 2016 and had a pre-HCT blood sample (N=973) available at the Center of International Blood and Marrow Transplant Research biorepository. PacBio sequencing and SNP-array genotyping were used to identify JAK2V617F mutation and associated mosaic chromosomal alterations (mCAs), respectively. Cox proportional hazard models were used for HCT outcome analyses. Genomic testing was complete for 924 MF patients (634 primary MF [PMF], 135 post-polycythemia vera [PPV-MF], and 155 post-essential thrombocytopenia [PET-MF]). JAK2V617F affected 562 patients (57.6% of PMF, 97% of PPV-MF, and 42.6% of PET-MF). Almost all patients with mCAs involving the JAK2 region (97.9%) were JAK2V617-positive. In PMF, JAK2V617F mutation status, allele burden, or identified mCAs were not associated with disease progression/relapse, non-relapse mortality (NRM), or overall survival. Almost all PPV-MF were JAK2V617F-positive (97%), with no association between HCT outcomes and mutation allele burden or mCAs. In PET-MF, JAK2V617F high mutation allele burden (≥60%) was associated with excess risk of NRM, restricted to transplants received in the era of JAK inhibitors (2013-2016; HR=7.65, 95% CI=2.10-27.82, p=0.002). Yet, allele burden was not associated with post-HCT disease progression/relapse or survival. Our findings support the concept that HCT can mitigate the known negative effect of JAK2V617F in MF patients, particularly for PMF and PPV-MF.
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6.
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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Full text
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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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7.
Transplant Outcomes of Myelofibrosis with Busulfan and Fludarabine Myeloablative Conditioning
Joseph, J., Srour, S. A., Milton, D. R., Ramdial, J. L., Saini, N. Y., Olson, A. L., Bashir, Q., Oran, B., Alousi, A. M., Hosing, C., et al
Transplantation and cellular therapy. 2023
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Full text
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Editor's Choice
Abstract
BACKGROUND Outcomes of myelofibrosis with allogeneic stem cell transplantation (allo-SCT) have improved over the past decade and are partly related to advances in supportive treatments and conditioning regimens. Several factors are known to predict transplant outcomes. However, most studies lack homogeneity in the conditioning regimen used, which limits their ability to assess prognostic factors on transplant outcomes. OBJECTIVE We aimed to determine the risk factors that predict transplant outcomes in patients with myelofibrosis who underwent matched or mismatched allo-SCT using a uniform myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis. STUDY DESIGN This single-center study included patients with myelofibrosis who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) and received busulfan and fludarabine conditioning with methotrexate/tacrolimus-based GVHD prophylaxis. RESULTS Sixty-five patients with myelofibrosis met the criteria and were included in the study. At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (HR [95% CI], 0.33 [0.11-0.99]; p = 0.048). For NRM, HCT-CI (≥3 vs. <3, 10.09 [2.09-48.76]; p=0.004) and donor type (MUD vs. MRD, 5.38 [1.14-25.30]; p=0.033 and MMUD vs. MRD, 10.73 [1.05-109.4]; p=0.045) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (≥3 vs. <3, 3.31 [1.22-8.99]; p = 0.019) and donor type (MMUD vs. MRD, 5.20 [1.35-19.98]; p = 0.016) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival but this didn't reach statistical significance (>12 months vs. ≤12 months: NRM, 7.20 [0.96-53.94]; p=0.055 and OS, 2.60 [0.95-7.14]; p=0.06). CONCLUSIONS In a homogenous cohort of myelofibrosis patients uniformly treated with busulfan/fludarabine myeloablative conditioning and methotrexate-based GVHD prophylaxis, we showed that donor choice and HCT-CI are the two strongest predictors for improved survival after allo-SCT.
PICO Summary
Population
People with myelofibrosis who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) at a single centre in USA (n=176)
Intervention
Cohort for analysis: all who received myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis (n=65)
Comparison
None
Outcome
At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (HR [95% CI], 0.33 [0.11-0.99]). For NRM, HCT-CI (>/=3 vs. <3, 10.09 [2.09-48.76]) and donor type (MUD vs. MRD, 5.38 [1.14-25.30] and MMUD vs. MRD, 10.73 [1.05-109.4]) were associated with an increased risk of mortality. Likewise for OS, HCT-CI (>/=3 vs. <3, 3.31 [1.22-8.99];) and donor type (MMUD vs. MRD, 5.20 [1.35-19.98]) were significantly associated with inferior survival. Longer time from diagnosis to allo-SCT seemed to confer worse survival but this didn't reach statistical significance (>12 months vs. </=12 months: NRM, 7.20 [0.96-53.94] and OS, 2.60 [0.95-7.14]).
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8.
Characterization of engraftment dynamics in myelofibrosis after allogeneic hematopoietic cell transplantation including novel conditioning schemes
Jungius, S., Adam, F. C., Grosheintz, K., Medinger, M., Buser, A., Passweg, J. R., Halter, J. P., Meyer, S. C.
Frontiers in oncology. 2023;13:1205387
Abstract
INTRODUCTION Myelofibrosis (MF) is a rare hematopoietic stem cell disorder progressing to bone marrow (BM) failure or blast phase. Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative therapy for a limited subset of patients with advanced MF, who are eligible, but engraftment in MF vs. AML is delayed which promotes complications. As determinants of engraftment in MF are incompletely characterized, we studied engraftment dynamics at our center. METHODS A longitudinal cohort of 71 allogeneic HCT performed 2000-2019 with >50% after 2015 was evaluated. RESULTS Median time to neutrophil engraftment ≥0.5x109/l was +20 days post-transplant and associated with BM fibrosis, splenomegaly and infused CD34+ cell number. Engraftment dynamics were similar in primary vs. secondary MF and were independent of MF driver mutations in JAK2, CALR and MPL. Neutrophil engraftment occurred later upon haploidentical HCT with thiotepa-busulfan-fludarabine conditioning, post-transplant cyclophosphamide and G-CSF (TBF-PTCy/G-CSF) administered to 9.9% and 15.6% of patients in 2000-2019 and after 2015, respectively. Engraftment of platelets was similarly delayed, while reconstitution of reticulocytes was not affected. CONCLUSIONS Since MF is a rare hematologic malignancy, this data from a large number of HCT for MF is essential to substantiate that later neutrophil and platelet engraftment in MF relates both to host and treatment-related factors. Observations from this longitudinal cohort support that novel conditioning schemes administered also to rare entities such as MF, require detailed evaluation in larger, multi-center cohorts to assess also indicators of long-term graft function and overall outcome in patients with this infrequent hematopoietic neoplasm undergoing allogeneic transplantation.
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Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EBMT/ELN International Working Group
Kröger, N., Bacigalupo, A., Barbui, T., Ditschkowski, M., Gagelmann, N., Griesshammer, M., Gupta, V., Hamad, N., Harrison, C., Hernandez-Boluda, J. C., et al
The Lancet. Haematology. 2023
Abstract
New options for medical therapy and risk scoring systems containing molecular data are leading to increased complexity in the management of patients with myelofibrosis. To inform patients' optimal care, we updated the 2015 guidelines on indications for and management of allogeneic haematopoietic stem-cell transplantation (HSCT) with the support of the European Society for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN). New recommendations were produced using a consensus-building methodology after a comprehensive review of articles released from January, 2015 to December, 2022. Seven domains and 18 key questions were selected through a series of questionnaires using a Delphi process. Key recommendations in this update include: patients with primary myelofibrosis and an intermediate-2 or high-risk Dynamic International Prognostic Scoring System score, or a high-risk Mutation-Enhanced International Prognostic Score Systems (MIPSS70 or MIPSS70-plus) score, or a low-risk or intermediate-risk Myelofibrosis Transplant Scoring System score should be considered candidates for allogeneic HSCT. All patients who are candidates for allogeneic HSCT with splenomegaly greater than 5 cm below the left costal margin or splenomegaly-related symptoms should receive a spleen-directed treatment, ideally with a JAK-inhibitor; HLA-matched sibling donors remain the preferred donor source to date. Reduced intensity conditioning and myeloablative conditioning are both valid options for patients with myelofibrosis. Regular post-transplantation driver mutation monitoring is recommended to detect and treat early relapse with donor lymphocyte infusion. In a disease where evidence-based guidance is scarce, these recommendations might help clinicians and patients in shared decision making.
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Upfront allogeneic transplantation versus JAK inhibitor therapy for patients with myelofibrosis: a North American collaborative study
Maze, D., Arcasoy, M. O., Henrie, R., Cerquozzi, S., Kamble, R., Al-Hadidi, S., Yacoub, A., Singh, A. K., Elsawy, M., Sirhan, S., et al
Bone marrow transplantation. 2023
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF) and is recommended for patients with higher risk disease. However, there is a risk of early mortality, and optimal timing is unknown. JAK inhibitor (JAKi) therapy may offer durable improvement in symptoms, splenomegaly and quality of life. The aim of this multicentre, retrospective observational study was to compare outcomes of patients aged 70 years or below with MF in chronic phase who received upfront JAKi therapy vs. upfront HCT in dynamic international prognostic scoring system (DIPSS)-stratified categories. For the whole study cohort, median overall survival (OS) was longer for patients who received a JAKi vs. upfront HCT, 69 (95% CI 57-89) vs. 42 (95% CI 20-not reached, NR) months, respectively (p = 0.01). In patients with intermediate-2 and high-risk disease, median OS was 55 (95% CI 36-73) months with JAKi vs. 36 (95% CI 20-NR) months for HCT (p = 0.27). An upfront HCT strategy was associated with early mortality and difference in median OS was not observed in any risk group by 5 years of follow-up. Within the limitations of a retrospective observational study, we did not observe any benefit of a universal upfront HCT approach for higher-risk MF.