[Show abstract][Hide abstract] ABSTRACT: Despite the overall benefit from allogeneic hematopoietic stem-cell transplantation observed in patients with poor cytogenetic risk acute myeloid leukemia in first complete remission, the precise effect of this procedure for different poor-risk subtypes has only been scarcely analyzed. This retrospective analysis was performed to investigate whether allogeneic hematopoietic stem-cell transplantation performed in first complete remission in patients with monosomal-karyotype can overcome their adverse prognosis. From a total of 4635 patients included in the study 189 (4%) harbored a monosomal-karyotype The presence of a monosomal-karyotype was associated with a worse outcome, with an inferior leukemia-free survival and overall survival (5-year leukemia-free survival and overall survival: 24+/-3% and 26+/-3% vs. 53+/-1% and 57±1% in monosomal-karyotype and non-monosomal-karyotype, respectively; p<0.0001) and higher relapse risk after transplantation (cumulative incidence of relapse at 5 years: 56+/-4% in monosomal-karyotype vs. 28+/-1% in non-monosomal-karyotype, p<0.0001). The adverse negative impact of monosomal-karyotype cytogenetics was confirmed in the entire cohort in a multivariate analysis (Hazard-Ratio:1.88, 95% confidence-interval:1.29-2.73, p=0.001 for relapse incidence; Hazard-Ratio:1.71, 95% confidence-interval:1.27-2.32, p<0.0001 for leukemia-free survival; Hazard-Ratio:1.81, 95% confidence-interval:1.32-2.48, p=0.0002 for overall survival), and was independent of the presence of other poor-risk cytogenetic subtypes. In summary, monosomal-karyotype arises as a strong negative prognostic feature in acute myeloid leukemia also in patients submitted to allogeneic hematopoietic stem-cell transplantation in first complete remission, stressing the need to develop additional pre- and post-transplantation strategies aimed to improved overall results. Nonetheless, allogeneic hematopoietic stem-cell transplantation in early phase is currently the best therapy for this very poor-risk acute myeloid leukemia subtype.
[Show abstract][Hide abstract] ABSTRACT: Patients with cytogenetically normal acute myeloid leukemia (CN-AML) can be subdivided by molecular mutations. However, data on the influence of combinations of different aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) is limited. Therefore, we performed a retrospective registry analysis on 702 adults with CN-AML undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1(mut)) and FLT3 internal tandem duplications (FLT3-ITD). Double negative patients were evaluated for mutations of the CCAAT/enhancer binding protein α gene (CEBPα). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. 2y-OS from HSCT was 81±5% in NPM1(mut)/FLT3(wt) (n=68), 75±3% in NPM1(wt)/FLT3(wt) (n=290), 66±3% in NPM1(mut)/FLT3-ITD (n=269) and 54±7% in NPM1(wt)/FLT3-ITD (n=75; p=0.003). Analysis of CEBPα among patients with NPM1(wt)/FLT3(wt) revealed excellent results both in patients with CEBPα(mut) (n=13, 2y-OS:100%), and with a triple negative genotype (n=138, 2y-OS:77±3%). In a Cox-model of predefined factors, older age, presence of FLT3-ITD and >1 course of chemotherapy to reach CR were associated with inferior outcome. 2y-OS/LFS were 88±3%/79±4% in patients without any, 77±2%/73±3% with one, and 53±4%/50±4 with>=2 risk factors (p=0.002 for LFS, p=0.003 for OS). Hence, FLT3-ITD proofed to be the decisive molecular marker for outcome after HSCT for CN-AML in CR1, regardless of NPM1 mutational status, variations of transplant protocols, or development of GvHD. Age, FLT3-ITD and response to induction chemotherapy allow for a prognostic risk classification.
[Show abstract][Hide abstract] ABSTRACT: Background: Cyclophosphamide plus intravenous busulfan has not been compared with cyclophosphamide plus total body irradiation (TBI) in adults with advanced refractory acute myeloid leukaemia before allogeneic haemopoietic stem-cell transplantation (HCT). We aimed to assess whether survival of patients receiving ablative intravenous busulfan-based conditioning regimens before a related or volunteer-unrelated donor HCT for refractory acute myeloid leukaemia is not inferior to that of patients receiving an ablative TBI-based regimen. Methods: In this retrospective, multicentre, registry-based study, we obtained data for patients (aged >18 years) with refractory acute myeloid leukaemia in active phase of disease, who had received HCT from an HLA-identical sibling or an unrelated donor after intravenous busulfan plus cyclophosphamide or cyclophosphamide plus TBI conditioning between 2000 and 2012. Data was obtained from the European Group for Blood and Marrow Transplantation registry. The primary endpoints of the study were overall survival and leukaemia-free survival. Findings: We obtained data for 514 patients who had received intravenous busulfan plus cyclophosphamide and 338 patients who had received cyclophosphamide plus TBI. The median percentage of blasts before HCT did not differ significantly between groups (20% [range 5-100; IQR 10-32] in the intravenous busulfan plus cyclophosphamide group vs 16% [5-95; 9-33] in the cyclophosphamide plus TBI group; p=0·16). Overall survival at 2 years did not differ between the groups in the univariate analysis (31·2% [95% CI 26·8-35·5] with intravenous busulfan plus cyclophosphamide vs 33·4% [28·1-38·7] wth cyclophosphamide plus TBI; p=0·65). Leukaemia-free survival at 2 years also did not differ between groups (25·0% [95% CI 21·0-29·0] vs 28·4% [23·4-33·5]; p=0·47). In multivariable analysis adjusting for differences between both groups, no difference was noted between the two groups in terms of overall survival (hazard ratio [HR] 0·99 [95% CI 0·83-1·20]; p=0·95) or leukaemia-free survival (HR 0·97 [0·81-1·16]; p=0·71). Main causes of non-relapse mortality were graft-versus-host disease (49 [10%] in the intravenous busulfan plus cyclophosphamide group vs 25 [7%] in the cyclophosphamide plus TBI group) and infection (36 [7%] vs 18 [5%]). Interpretation: From a practical standpoint, the use of intravenous busulfan plus cyclophosphamide is likely to be a valid and efficient alternative to cyclophosphamide plus TBI conditioning regimen for patients with refractory acute myeloid leukaemia, especially for those transplant centres without access to radiation facilities. Funding: None.
[Show abstract][Hide abstract] ABSTRACT: Acute myeloid leukemia (AML) with 11q23/MLL rearrangement (MLL-r AML) is allocated to the intermediate or high-risk cytogenetic prognostic category depending on the MLL fusion partner. A more favourable outcome has been reported in patients receiving an allogeneic hematopoietic stem-cell transplantation (alloHSCT), but this has not been confirmed in large series. We analyzed the outcome of alloHSCT among adult patients reported to the ALWP between 2000 and 2010. We identified 159 patients with 11q23/MLL rearranged AML allografted in first complete remission (CR1, n=138) or CR2, mostly corresponding to t(9;11), t(11;19), t(6;11), and t(10;11) translocations. Two-year overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and non-relapse mortality (NRM) was 56±4%, 51±4%, 31±3%, and 17±4%, respectively. The outcome differed according to 11q23/MLL rearrangement, being more favourable in patients with t(9;11) and t(11;19) compared to t(10;11) and t(6;11) (2-year OS: 64±6% and 73±10% vs 40±13% and 24±11%, respectively; P<0.0001). Multivariate analysis for OS identified t(6;11), t(10;11), age>40 years and CR2 as unfavourable features, whereas t(6;11), t(10;11), CR2 and the use of RIC regimen affected poorly LFS. This study confirms the potential role of alloHSCT for adult patients with 11q23/MLL rearranged AML in CR1.Leukemia accepted article preview online, 17 June 2015. doi:10.1038/leu.2015.143.
No preview · Article · Jun 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: In recipients of allogeneic hematopoietic stem cell transplantation with AML in CR1, reduced intensity (RIC) conditioning regimens are usually given to older patients and myeloablative regimens (MAC) to younger patients. We analyzed whether in middle-aged patients aged 40-60 years, MAC was superior to RIC in cytogenetically higher risk AML. Among 2974 patients, 1638 had MAC and 1336 RIC transplants. Cytogenetics were high risk in 508, intermediate risk in 2297 and low risk in 169. Overall survival (OS) was higher in patients with RIC with low-risk cytogenetics but not in the intermediate- or poor-risk AML. Relapse incidence was lower with MAC in poor- and intermediate-risk AML. Nonrelapse mortality (NRM) was higher in MAC in all cytogenetic risk groups. Multivariate analysis confirmed a significant leukemia-free survival and OS advantage for RIC in low risk but no advantage of MAC in intermediate- and poor-risk leukemia. In patients aged 40-60 years, MAC has no advantage over RIC. We confirm lower relapse but higher NRM risks with MAC. MAC is not superior in patients with higher risk cytogenetics, but is inferior to RIC in the small cohort of AML patients with low-risk cytogenetics.Bone Marrow Transplantation advance online publication, 1 June 2015; doi:10.1038/bmt.2015.121.
No preview · Article · Jun 2015 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: We performed a retrospective analysis of the European Group for Blood and Marrow Transplantation database comparing the outcomes of multiple myeloma patients who received tandem autologous followed by allogeneic PSCT (auto-allo) with the outcomes of patients who underwent a reduced intensity conditioning allograft (early RIC) without prior autologous transplant. From 1996 to 2013, we identified a total of 690 patients: 517 patients were planned to receive auto-allo and 173 received an early RIC allograft without prior autologous transplant. With a median follow-up of 93 months, 5-year PFS survival was significantly better in the auto-allo group, 34% compared with 22% in the early RIC group (P<0.001). OS was also significantly improved in the auto-allo group with a 5-year rate of 59% vs 42% in the early RIC group (P=0.001). The non-relapse mortality rate was lower in the auto-allo group than in the early RIC group, with 1- and 3-year rates of 8% and 13% vs 20% and 28%, respectively (P<0.001). The relapse/progression rate was similar in the two groups, with 5-year rates of 50% for auto-allo and 46% for early RIC (P=0.42). These data suggest that planned tandem autologous allograft can improve overall survival compared with upfront RIC allograft alone in patients with multiple myeloma.Bone Marrow Transplantation advance online publication, 23 March 2015; doi:10.1038/bmt.2015.45.
No preview · Article · Mar 2015 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: Thiotepa is an alkylating compound with an antineoplastic and myeloablative activity and can mimic the effect of radiation. However, it is unknown whether this new regimen could safely replace the long-established ones. This retrospective matched-pair analysis evaluated the outcome of adults with acute myeloid leukemia in first complete remission who received myeloablative conditioning either with a thiotepa-based (n=121) or a cyclophosphamide/total body irradiation-based (TBI; n=358) regimen for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling or an unrelated donor. With a median follow-up of 44 months, the outcome was similar in both groups. Acute graft-versus-host disease grade II-IV was observed in 25% after thiotepa-containing regimen versus 35% after TBI (p=0.06). The 2-year cumulative incidence of chronic graft-versus-host disease was 40.5% for thiotepa and 41% for TBI (p=0.98). At 2 years, the cumulative incidences of non-relapse mortality and relapse incidence were 23.9% (thiotepa) versus 22.4% (TBI; p=0.66) and 17.2% (thiotepa) versus 23.3% (TBI; p=0.77), retrospectively. The probabilities of leukemia-free and overall survival at 2 years were not significantly different between the thiotepa and TBI groups, at 58.9% versus 54.2% (p=0.95) and 61.4% versus 58% (p=0.72), respectively. Myeloablative regimens using combinations including thiotepa can provide satisfactory outcomes but the optimal conditioning remains unclear for the individual patient in this setting. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Mar 2015 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: Previous studies have shown that obtaining complete hematologic remission (CR) in multiple myeloma is an important predictor of PFS and OS. This applies both to autologous and allogeneic transplantation. However, the importance of CR obtained before vs after second transplant or following allogeneic vs autologous transplantation is not clear. We investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional prospective study comparing tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation-single or double (auto/auto). Allocation to treatment was performed according to availability of a matched sibling donor. Cox regression and multi-state models were applied. The long-term probability of survival in CR was superior in auto/RICallo, both comparing groups according to treatment allocated at start (28.8 vs 11.4% at 60 months, P=0.0004) and according to actual administration of second transplant (25.6 vs 9.6% at 60 months, P=0.008). CR achieved before the second transplant was predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047) irrespective of the type of second transplant. CR achieved after auto/RICallo was more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81, P=0.390), indicating a better durability of CR obtained after an allotransplant procedure.Bone Marrow Transplantation advance online publication, 26 January 2015; doi:10.1038/bmt.2014.310.
No preview · Article · Jan 2015 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: One-hundred and forty patients who had received HSCT for MDS or AML transformation following treatment of severe aplastic anemia (SAA) were identified in the EBMT database. The median age at HSCT was 29 years (1-66). Donors were related in 49% and unrelated in 51% cases. The 5 years probability of relapse and non-relapse mortality was 17% and 41%, respectively. The five-year overall survival was 45 + 9%, better for patients untreated or in remission than in patients with refractory disease. Allogeneic HSCT leads to prolonged survival in close to half of the patients transforming to MDS or AML from SAA.
No preview · Article · Sep 2014 · Biology of Blood and Marrow Transplantation