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Outcome of Patients with Fanconi Anemia developing myelodysplasia and acute leukemia who received Allogeneic Hematopoietic Stem Cell Transplantation: A retrospective analysis on Behalf of EBMT group
Giardino, S., Peffault de Latour, R., Aljurf, M., Eikema, D. J., Bosman, P., Bertrand, Y., Tbakhi, A., Holter, W., Bornhauser, M., Rossig, C., et al
American journal of hematology. 2020
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo-HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre-HSCT cytoreductive therapies and related toxicities, disease status pre-HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5-year OS and EFS were 42% (30-53%) and 39% (27-51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48-95] vs 37% [24-50],P = .04), while none of the other variables considered had an impact. Twenty-two patients received pre-HSCT cytoreduction and 9/22 showed a grade 3-4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre-HSCT 48% [20-75%] vs no-toxicity 51% [25-78%],P = .98). The cumulative incidence of day-100 grade II-IV a-GvHD and of 5-year c-GvHD were 38% (26-50%) and 40% (28-52%). Non-relapse-related mortality and incidence of relapse at 5-years were 40% (29-52%) and 21% (11-30%) respectively, without any significant impact of the tested variables. Causes of death were transplant-related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre-HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre-HSCT should be considered if a donor have been secured. This article is protected by copyright. All rights reserved.
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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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A prospective non-interventional study on the impact of transfusion burden and related iron toxicity on outcome in myelodysplastic syndromes undergoing allogeneic hematopoietic cell transplantation()
Cremers, E. M. P., de Witte, T., de Wreede, L., Eikema, D. J., Koster, L., van Biezen, A., Finke, J., Socie, G., Beelen, D., Maertens, J., et al
Leukemia & lymphoma. 2019;:1-10
Abstract
Most myelodysplastic syndromes (MDS)-patients receive multiple red blood cell transfusions (RBCT). Transfusions may cause iron-related toxicity and mortality, influencing outcome after allogeneic HSCT. This prospective non-interventional study evaluated 222 MDS and CMML patients undergoing HSCT. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence (RI) at 36 months were 52%, 44%, 25%, and 31%, respectively. Age, percentage of marrow blasts and severe comorbidities impacted OS. RFS was significantly associated with RBCT burden prior to HSCT (HR: 1.7; p = .02). High ferritin levels had a significant negative impact on OS and RI, but no impact on NRM. Administration of iron chelation therapy prior to HSCT did not influence the outcome, but early iron reduction after HSCT (started before 6 months) improved RFS significantly after transplantation (56% in the control group vs. 90% in the treated group, respectively; p = .04). This study illustrates the impact of RBCT and related parameters on HSCT-outcome. Patients with an expected prolonged survival after transplantation may benefit from early iron reduction therapy after transplantation.
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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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Myeloablative and Reduced-intensity conditioned Allogeneic Haematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of EBMT
McLornan, D., Szydlo, R., Koster, L., Chalandon, Y., Robin, M., Wolschke, C., Beelen, D., Socie, G., Bornhauser, M., Angelucci, E., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
This retrospective study by the EBMT analysed the outcome of 2224 Myelofibrosis patients who underwent allogeneic stem cell transplantation (allo-SCT) between 2000-2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced intensity conditioning (RIC). Median patient age was 52.9 years (r, 18-74) and 57.5 years (range(r), 21-76) in the MAC and RIC cohorts respectively. Donor type was similar: matched sibling donors (MAC- 317 (41%)) and RIC- 552 (38%) and unrelated donors (UD; MAC (464 (59%); RIC- 891 (62%)). Median time to both neutrophil and platelet (>20x10(9)/L) engraftment did not differ between cohorts. Rates of grade II-IV acute (a) GVHD were 28% (MAC) and 31% (RIC; (p=ns). Cumulative cGVHD rates (limited/ extensive) were 22%/27% (MAC) and 19%/ 31% (RIC; p=0.10). Cumulative incidences of Non-relapse mortality (NRM) at 1, 3 and 5-years were: 25.5%, 32.2% and 34.6% (MAC) and 26.3%, 32.8% and 34.4% (RIC). There was a trend towards a higher relapse rate with RIC regimens compared to MAC (p=0.08); rates at 1, 3 and 5-years were: 10.9%, 17.2% and 20.1% (MAC) and 14%, 19.7% and 23.2% (RIC), respectively. No significant difference in 5yr probabilities of overall survival (OS) was noted: MAC 53.0% (95% confidence intervals (CI) 49.1-56.9) and RIC 51.0% (95% CI: 48.3-53.7); p=0.78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI: 29.0-36.1) in the MAC group and 26.1% (95% CI: 23.9-28.2) in the RIC group (p=0.001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 yrs), using an unrelated donor and a Karnofsky Performance Status (KPS) of 80 or less. For the RIC cohort, worse OS and NRM was associated with age 60- 70 years when compared to younger recipients, use of a mismatched donor and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend towards less relapse and an overall suggested advantage of improved GRFS; albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient and optimisation to reduce significant relapse and NRM rates are required.