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Unrelated or haploidentical allogeneic hematopoietic cell transplantation in second complete remission for acute myeloid leukemia-Improved outcomes over time: A European Society for Blood and Marrow Transplantation Acute Leukemia Working Party study
Al Hamed, R., Ngoya, M., Galimard, J. E., Sengeloev, H., Gedde-Dahl, T., Kulagin, A., Platzbecker, U., Yakoub-Agha, I., Byrne, J. L., Valerius, T., et al
Cancer. 2023
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (allo-HCT) is the only cure for acute myeloid leukemia (AML) in second complete remission (CR2). Patients lacking a matched sibling donor (MSD) receive transplants from matched unrelated donors (MUDs), mismatched unrelated donors (MMUDs), haploidentical (haplo) donors, or cord blood. METHODS This is a retrospective, registry-based European Society for Blood and Marrow Transplantation study that investigates changes in patient- and transplant-related characteristics and posttransplant outcomes over time. RESULTS We identified 3955 adult patients (46.7% female; median age, 52 years [range, 18-78 years]) with AML in CR2 first transplanted between 2005 and 2019 from a MUD 10/10 (61.4%), MMUD 9/10 (21.9%), or haplo donor (16.7%) and followed for 3.7 years. A total of 725 patients were transplanted between 2005 and 2009, 1600 between 2010 and 2014, and 1630 between 2015 and 2019. Over the three time periods, there was a significant increase in patient age (from 48.7 to 53.5 years; p < .001), use of a haplo donor (from 4.6% to 26.4%; p < .001), and use of posttransplant cyclophosphamide (from 0.4% to 29%; p < .001). There was a significant decrease in total body irradiation and in vivo T-cell depletion. In multivariate analysis, transplants performed more recently had better outcomes. Leukemia-free survival (hazard ratio [HR], 0.79; p = .002) and overall survival (HR, 0.73; p < .001) increased over time. Similarly, nonrelapse mortality (HR, 0.64; p < .001) decreased over time. We also observed better graft-vs-host disease (GVHD) rates (acute GVHD II-IV: HR, 0.78; p = .03; GVHD-free, relapse-free survival: HR, 0.69; p < .001). CONCLUSIONS Even in the absence of an MSD, outcomes of allo-HCT in CR2 for AML have significantly improved over time, with most favorable outcomes achieved with a MUD.
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Inferior outcome of allogeneic stem cell transplantation for secondary acute myeloid leukemia in first complete remission as compared to de novo acute myeloid leukemia
Schmaelter, A. K., Labopin, M., Socie, G., Itala-Remes, M., Blaise, D., Yakoub-Agha, I., Forcade, E., Cornelissen, J., Ganser, A., Beelen, D., et al
Blood cancer journal. 2020;10(3):26
Abstract
Following chemotherapy, secondary acute myeloid leukemia (sAML), occurring after antecedent hematologic diseases, previous chemotherapy or radiation, has an inferior prognosis compared with de novo AML. To define the outcome of sAML in the context of allogeneic stem cell transplantation (alloSCT), a retrospective, registry-based comparison was performed, including 11,439 patients with de novo and 1325 with sAML. Among transplants in first complete remission (CR1) (n = 8,600), the 3-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 28.5% and 16.4% for de novo, and 35% and 23.4% for sAML. Three-year overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 1.33 [95% CI = 1.21-1.48]; p < 10(-5)), LFS (HR = 1.32 [95% CI = 1.19-1.45]; p < 10(-5)) and GRFS (HR = 1.2 [95% CI = 1.1-1.31]; p < 10(-4)) and higher NRM (HR = 1.37 [95% CI = 1.17-1.59]; p < 10(-4)) and RI (HR = 1.27 [95% CI = 1.12-1.44]; p < 10(-3)). Results of the Cox model were confirmed in a matched-pair analysis. In contrast, results did not differ between de novo and sAML after alloSCT in induction failure or relapse. Hence, this analysis identified sAML as an independent risk factor for outcome after alloSCT in CR1.
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3.
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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Prognostic significance of recurring chromosomal abnormalities in transplanted patients with acute myeloid leukemia
Canaani, J., Labopin, M., Itala-Remes, M., Blaise, D., Socie, G., Forcade, E., Maertens, J., Wu, D., Malladi, R., Cornelissen, J. J., et al
Leukemia. 2019
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Editor's Choice
Abstract
Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor. Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Our analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.
PICO Summary
Population
8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor, reported to the ALWP/EBMT registry.
Intervention
Patients with monosomal karyotype (n=533) or complex karyotype (n= 507) or other abnormalities
Comparison
Patients with a normal karyotype (n=4530)
Outcome
Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. This analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.
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Transplant outcomes for patients with therapy-related acute myeloid leukemia with prior lymphoid malignancy: an ALWP of EBMT study
Gatwood, K. S., Labopin, M., Savani, B. N., Finke, J., Socie, G., Beelen, D., Yakoub-Agha, I., Chevallier, P., Ganser, A., Blaise, D., et al
Bone marrow transplantation. 2019
Abstract
Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for patients with secondary acute myeloid leukemia (sAML), though the impact of conditioning regimens on HCT outcomes for patients with antecedent lymphoid malignancy is largely unknown. This multicenter, retrospective registry study of the ALWP of the EBMT assessed HCT outcomes in this population. In all, 549 patients ≥18 years with sAML following an antecedent lymphoid malignancy treated with first allograft between 2000-2016 were included. Myeloablative (MAC) and reduced intensity conditioning (RIC) was given in 258 (47%) and 291 (53%), respectively. At 2 years, leukemia-free survival (LFS) was 31.7% (95% CI, 27.5-35.9), overall survival (OS) was 37.4% (95% CI, 33-41.8), nonrelapse mortality (NRM) was 28.9% (95% CI, 25-33), and GVHD-free, relapse-free survival (GRFS) was 22.8% (95% CI, 19-26.6). In multivariate analysis, patients receiving RIC regimens had lower risk of NRM (HR: 0.58, CI: 0.40-0.83, p = 0.003), and improved LFS (HR: 0.67, CI: 0.52-0.85, p = 0.001). Patients with prior autologous HCT had inferior LFS (HR: 1.30, CI: 1.01-1.67, p = 0.01). This study demonstrates that sAML patients following prior lymphoid malignancy treated with RIC regimens have a lower risk of NRM and improved LFS, OS, and GFRS. Other variables associated with inferior outcomes include older age, active disease, adverse cytogenetics, and prior auto-HCT.
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Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lymphoblastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT
Pavlu, J., Labopin, M., Niittyvuopio, R., Socie, G., Yakoub-Agha, I., Wu, D., Remenyi, P., Passweg, J., Beelen, D. W., Aljurf, M., et al
Journal of hematology & oncology. 2019;12(1):108
Abstract
BACKGROUND Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. METHODS In this retrospective registry study, we explored whether measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia is associated with different outcomes in recipients of myeloablative total body irradiation (TBI)-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18-72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated donors. RESULTS In 1816 of patients, no disease was detectable, and in 964 patients, MRD was positive. Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02-1.39), 1.26 (1.1-1.44), and 1.51 (1.26-1.8). TBI was associated with a higher OS, LFS, and lower RI with HR of 0.75 (0.62-0.90), 0.70 (0.60-0.82), and 0.60 (0.49-0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS and LFS and higher RI in the TBI group, and with higher RI in the chemotherapy group. TBI-based conditioning was associated with improved outcomes in both MRD-negative and MRD-positive patients. CONCLUSIONS In this large study, we confirmed that patients who are MRD-negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI-based conditioning in the myeloablative setting.
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Haploidentical transplantation and posttransplant cyclophosphamide for treating aplastic anemia patients: a report from the EBMT Severe Aplastic Anemia Working Party
Prata, P. H., Eikema, D. J., Afansyev, B., Bosman, P., Smiers, F., Diez-Martin, J. L., Arrais-Rodrigues, C., Koc, Y., Poire, X., Sirvent, A., et al
Bone marrow transplantation. 2019
Abstract
In the absence of an HLA-matched donor, the best treatment for acquired aplastic anemia patients refractory to immunosuppression is unclear. We collected and analyzed data from all acquired aplastic anemia patients who underwent a haploidentical transplantation with posttransplant cyclophosphamide in Europe from 2011 to 2017 (n = 33). The cumulative incidence of neutrophil engraftment was 67% (CI95%: 51-83%) at D +28 and was unaffected by age group, stem cell source, ATG use, or Baltimore conditioning regimen. The cumulative incidence of grades II-III acute GvHD was 23% at D +100, and limited chronic GvHD was 10% (0-20) at 2 years, without cases of grade IV acute or extensive chronic GvHD. Two-year overall survival was 78% (64-93), and 2-year graft-versus-host disease-free survival was 63% (46-81). In univariate analysis, the 2-year OS was higher among patients who received the Baltimore conditioning regimen (93% (81-100) versus 64% (41-87), p = 0.03), whereas age group, stem cell source, and ATG use had no effect. Our results using unmanipulated haploidentical transplantation and posttransplant cyclophosphamide for treating refractory AA patients are encouraging, but warrant confirmation in a prospective study with a larger number of patients and longer follow-up.
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Outcomes of Salvage Haploidentical Transplant with Post-transplant Cyclophosphamide for Rescuing Graft Failure Patients: a Report on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy
Prata, P. H., Resche-Rigon, M., Blaise, D., Socie, G., Rohrlich, P. S., Milpied, N., Turlure, P., Nguyen, S., Sirvent, A., Bulabois, C. E., 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
Prognosis of patients with graft failure is dismal, and re-transplantation is the sole option for long-term survival. To address the interest of haploidentical transplantation as a salvage option in this context, we analyzed data from 24 patients with graft failure or loss re-transplanted with a haploidentical donor who received post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease prophylaxis (GvHD). Fludarabine-based reduced intensity conditioning was used in 23 patients, and 14 patients received the Baltimore regimen. The median delay between previous and salvage transplantation for graft failure was 63 (39-98) days. Besides PT-Cy, all patients received cyclosporine, and 22 patients also received MMF for GvHD prophylaxis. With a median follow up of 353 (16-2010) days, 1-year OS was 56% (95% CI: 38 - 81). Transplant complications accounted for 80% of deaths. The cumulative incidence of neutrophil engraftment was +30 was 79%. Cumulative incidence of grade II-IV acute GvHD at day-100 was 14%, and 1-year CI of chronic GvHD was 31%. One-year CI of relapse was 13%. Stem cell source did not impact on engraftment, GvHD, relapse nor overall survival. Salvage haploidentical transplant with PT-Cy for rescuing graft failure patients leads to an acceptable 1-year OS and might be a valid option in this poor situation.
PICO Summary
Population
Patients with graft failure or loss (n=24)
Intervention
Re-transplantation with a haploidentical donor who received post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease prophylaxis.
Comparison
None
Outcome
With a median follow up of 353 days, 1-year OS was 56%. Transplant complications accounted for 80% of deaths. The cumulative incidence of neutrophil engraftment was +30 was 79%. Cumulative incidence of grade II-IV acute GvHD at day-100 was 14%, and 1-year CI of chronic GvHD was 31%. One-year CI of relapse was 13%. Stem cell source did not impact on engraftment, GvHD, relapse nor overall survival.
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Allogeneic stem cell transplantation for blast crisis chronic myeloid leukemia in the era of tyrosine kinase inhibitors - A retrospective study by the EBMT Chronic Malignancies Working Party
Radujkovic, A., Dietrich, S., Blok, H. J., Nagler, A., Ayuk, F., Finke, J., Tischer, J., Mayer, J., Koc, Y., Sora, F., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
The prognosis of patients with blast crisis (BC) chronic myeloid leukemia (CML) is still dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option, but data on transplant outcomes are scarce. We therefore conducted a retrospective, registry based study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. A total of 170 patients allografted for BC CML after tyrosine kinase inhibitor pre-treatment between 2004 and 2016 were analyzed. Prior to transplant, 95 patients were in remission, whereas 75 patients had active BC. In multivariable analysis of the entire cohort, active BC at transplant was the strongest factor associated with decreased overall survival (OS, HR 1.87, P=0.010) and shorter leukemia-free survival (LFS, HR 1.69, P=0.017). For patients with BC in remission at transplant, advanced age (≥45 years), lower performance status (≤80%), longer interval from diagnosis BC to transplant (>12 months), myeloablative conditioning, and unrelated donor (UD) transplant were risk factors for inferior survival. In patients with active BC, only UD transplant was significantly associated with prolonged LFS and trended towards improved OS. In summary, survival of patients allografted for BC CML was strongly dependent on the pre-transplant remission status. In patients with remission of BC, conventional prognostic factors remained the major determinants of outcome, whereas in those with active BC at transplant, UD transplantation was associated with prolonged LFS in our study.
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Allogeneic stem cell transplantation in second complete remission for core binding factor acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Halaburda, K., Labopin, M., Mailhol, A., Socie, G., Craddock, C., Aljurf, M., Beelen, D., Cornelissen, J. J., Bourhis, J. H., Labussiere-Wallet, H., et al
Haematologica. 2019
Abstract
Core binding factor acute myeloid leukemia comprises two subtypes with distinct cytogenetic abnormalities of either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22). Since long-term response to chemotherapy in those leukemias is relatively good, allogeneic hematopoietic stem cell transplantation is considered in patients who relapse and achieve second complete remission. To evaluate the outcomes of allogeneic transplantation in this indication, we studied 631 patients in reported to the European Society for Blood and Marrow Transplantation Registry between the years 2000 and 2014. Leukemia-free survival probabilities at 2 and 5 years were 59.1% and 54.1%, while overall survival probabilities were 65% and 58.2% respectively. The incidence of relapse and risk of non-relapse mortality at the same time-points were 19.8% and 22.5% for relapse and 20.9% and 23.3% for non-relapse mortality respectively. The most important adverse factors influencing leukemia-free and overall survival were leukemia with t(8;21), presence of 3 or more additional chromosomal abnormalities and Karnofsky performance score <80. Relapse risk was increased in t(8;21) leukemia and associated with additional cytogenetic abnormalities as well as reduced intensity conditioning. Measurable residual disease in molecular evaluation before transplantation was associated with increased risk of relapse and inferior leukemia-free survival.