[Show abstract][Hide abstract] ABSTRACT: Successful allogeneic hematopoietic stem cell transplantation (HSCT) depends not only on good HLA match but also on T-cell mediated graft-versus-leukemia (GvL) effect. Nat-ural killer (NK) cells are able to kill malignant cells by receiving activation signal from the killer-cell immunoglobulin-like receptors (KIR) recognizing HLA molecules on a cancer cell. It has been recently reported that the risk of relapse in allogeneic hematopoietic stem cell transplantation (HSCT) is reduced in acute myeloid leukemia (AML) patients whose donors have several activating KIR genes or KIR B-motifs in unrelated donor setting, obvi-ously due to enhanced GvL effect by NK cells. We studied the effect on relapse rate of donor KIR haplotypes in the HLA-identical adult sibling HSCT, done in a single center, in Helsinki University Central Hospital, Helsinki, Finland. Altogether, 134 patients with 6 different diag-noses were identified. Their donors were KIR genotyped using the Luminex and the SSP techniques. The clinical endpoint, that is, occurrence of relapse, was compared with the presence or absence of single KIR genes. Also, time from transplantation to relapse was analyzed. The patients with AML whose donors have KIR2DL2 or KIR2DS2 had statistically significantly longer relapse-free survival (P = 0.015). Our data support previous reports that donors with KIR B-haplotype defining genes have a lower occurrence of relapse in HSCT of AML patients. Determination of donor KIR haplotypes could be a useful addition for a risk assessment of HSCT especially in AML patients.
[Show abstract][Hide abstract] ABSTRACT: Acquired chromosomal abnormalities are important prognostic factors in patients with myelodisplastic syndromes treated with supportive care and with disease modifying therapeutic interventions, including allogeneic hematopoietic stem cell transplantation. To assess the prognostic impact of cytogenetic characteristics after hematopoietic stem cell transplantation accurately, we investigated a homogeneous group of 523 patients with primary myelodisplastic syndromes who have received stem cells from Human Leukocyte Antigen-identical siblings. Overall survival at 5-years from transplantation in good-, intermediate-, and poor cytogenetic risk groups according to the International Prognostic Scoring System was 48%, 45% and 30%, respectively (p <0.01). Both the disease status (complete remission versus not in complete remission) and the morphological classification at transplant in the untreated patients were significantly associated with probability of overall survival and relapse-free survival (p <0.01). The cytogenetic risk groups have no prognostic impact in untreated patients with refractory anemia +/- ringed sideroblasts (p=0.90). However, combining the good and intermediate cytogenetic risk groups and comparing them to the poor risk group, showed within the other three disease-status-at-transplant groups, a hazard ratio of 1.86 (95% C.I. 1.41-2.45). In conclusion, this study shows that, in a large series of patients with primary myelodysplastic syndromes, poor-risk cytogenetics as defined by standard International Prognostic Scoring System is associated with a relatively poor survival after allogeneic stem cell transplantation from Human Leukocyte Antigen-identical siblings except in patients who are transplanted in Refractory Anemia/Refractory Anemia with Ringed Sideroblasts stage before progression to higher myelodysplastic syndrome stages.
[Show abstract][Hide abstract] ABSTRACT: Female donors for male recipients worsen the outcome of allogeneic hematopoietic stem-cell transplantation. We wanted to find out whether a male human leukocyte antigen (HLA)-matched unrelated donor (MUD, 8/8, n=2,014) might be an alternative to a female HLA-identical sibling donor (n=2,656) for male patients with acute leukemia.
This is a retrospective analysis from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation.
The relative risk (RR) of acute graft-versus-host disease (GVHD) of grades II to IV was increased in the MUD group with acute myeloid leukemia (AML) (RR, 1.47; P<0.001) and acute lymphoblastic leukemia (ALL) (RR, 1.76; P<0.001). There was no difference in incidence of chronic GVHD and nonrelapse mortality between the two groups. Probability of relapse was lower in the MUD group than in the sibling group in patients with ALL (hazards ratio [HR], 0.75; P=0.04) but not in the AML patients (HR, 0.89; P=0.17). Survival was not different between the groups. Leukemia-free survival (LFS) was also similar in the sibling and MUD groups in patients with AML (HR, 1.01; P=0.81) or ALL (HR, 0.93; P=0.45). Factors significantly associated with reduced LFS included active disease, poor cytogenetics, age, year of hematopoietic stem-cell transplantation, reduced-intensity conditioning, and the use of antithymocyte globulin.
Male patients who received grafts from male MUDs demonstrated an increased incidence of acute GVHD and LFS same as when using HLA-identical female donors.
[Show abstract][Hide abstract] ABSTRACT: Autologous stem cell transplantation (autoSCT) is considered a standard treatment for non-frail patients with mantle cell lymphoma (MCL), but little is known about outcome of MCL patients relapsing after autoSCT. We therefore sought to analyse the outcome after autoSCT failure and the efficacy of a rescue SCT in this setting.
Patients with MCL were eligible if they had relapsed after autoSCT performed between 2000 and 2009. 1054 patients could be identified in the EBMT registry. By contacting the transplant centres a full data set could be retrieved for 360 patients.
Median overall survival (OS) after relapse of the whole study group was 19 months. A long (>12 months) interval between autoSCT and relapse (p<0.001; HR 0.62), primary refractory disease (p<0.02, HR 1.92), prior high-dose ARA-C treatment (0.04, HR 1.43) and the year of relapse (0.02 HR 0.92) significantly influenced OS from relapse in multivariate analysis.Eighty patients (22%) received a rescue allogeneic SCT (alloSCT). Relapse incidence, non-relapse mortality, and OS 2 years after alloSCT was 33% (CI 21-45%), 30% (CI 19-42%) and 46% (CI 33-59%), respectively. Remission duration after autoSCT was the only variable significantly affecting the outcome of salvage alloSCT. In contrast, rescue autoSCT was not associated with long-term disease control. However, individual patients survived long-term even without salvage transplantation.
MCL recurrence within one year after autoSCT has an extremely dismal outcome, whilst the prognosis of patients with longer remission durations after autoSCT is significantly better. AlloSCT may offer the possibility of durable survival when performed for patients with a remission duration of more then 12 months after first autoSCT, but the favourable effect of a salvage alloSCT in this setting needs further validation.
[Show abstract][Hide abstract] ABSTRACT: The clinical course of polycythemia vera and essential thrombocythemia is potentially associated with long-term severe complications, such as evolution to myelofibrosis or acute myeloid leukemia. Allogeneic stem cell transplantation is currently the only potentially curative treatment for advanced polycythemia vera or essential thrombocythemia. We analyzed 250 consecutive patients with an initial diagnosis of polycythemia vera (n=120) or essential thrombocythemia (n=130), who underwent transplantation due to progression to myelofibrosis (n=193) or acute myeloid leukemia (n=57) and reported to European Group for Blood and Marrow Transplantation registry between 1994 and 2010. The median age was 56 years (range 22-75) and 52% of patients had an interval from diagnosis to transplant of 10 years or more. With a median follow-up from transplantation of 13 months, 3 years overall survival and relapse incidence were 55% and 32%, respectively. In the univariate analysis, the main parameters that negatively affected post-transplantation outcomes were older age (>55 years), a diagnosis at transplant of acute myeloid leukemia and the use of an unrelated donor. The 3 years cumulative incidence of non-relapse mortality was 28%, significantly higher in older patients (>55years, 35% vs. 20%, p=0.032), in unrelated compared to related donor (34% vs. 18%, p=0.034) and in diagnosis of acute myeloid leukemia compared to myelofibrosis (29% vs. 27%, p=0.045). This large retrospective study confirms that transplantation is potentially curative for end-stage polycythemia vera /essential thrombocythemia patients progressing to myelofibrosis or acute myeloid leukemia. Relapse and non-relapse mortality remain unsolved problems for which innovative treatment approaches need to be assessed.
[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.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 01/2014;
[Show abstract][Hide abstract] ABSTRACT: We analyzed the prognostic impact of donor and recipient cytomegalovirus (CMV) serostatus in 16628 de novo acute leukemia patients after allogeneic stem cell transplantation (allo-SCT). In comparison to CMV-seronegative recipients allografted from a CMV-seronegative donor, cases with CMV seropositivity of the donor and/or the recipient showed a significantly decreased 2-year leukemia-free survival (44% versus 49%, P < .001) and overall survival (50% versus 56%, P < .001), and increased non-relapse mortality (23% versus 20%, P < .001). Both groups showed a comparable relapse incidence and 2-year probability of graft-versus-host disease. The negative prognostic effects of CMV seropositivity of the donor and/or the recipient (versus CMV seronegativity of both) were significantly stronger for acute lymphoblastic leukemia (ALL) than for acute myeloid leukemia (AML), resulting in a markedly reduced 2-year overall survival (46% versus 55% for ALL compared to 52% versus 56% for AML). The important prognostic impact of donor/recipient CMV serostatus remained in a multivariate Cox regression analysis including the other prognostic variables. We conclude that donor and/or recipient CMV seropositivity is still associated with an adverse prognosis in de novo acute leukemia patients after allo-SCT despite the implementation of sophisticated strategies for prophylaxis, monitoring and (preemptive) treatment of CMV.
[Show abstract][Hide abstract] ABSTRACT: Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable bioavailability and a safer toxicity profile than the oral formulation. Comparative studies of outcomes have been performed between oral Bu/Cy and Cy/TBI, but there have been no comparative trials in the era of IV Bu.
We performed a retrospective registry-based study comparing outcomes of patients with AML in first or second remission after alloSCT from sibling donors who underwent IV Bu/Cy (n = 795) or Cy/TBI (n = 864) conditioning.
Engraftment rate was 98% and 99% after IV Bu/Cy and Cy/TBI, respectively. Grade 2 to 4 acute graft-versus-host disease (GVHD) was significantly lower in the IV Bu/Cy compared with Cy/TBI group (P < .001). Similarly, chronic GVHD was significantly lower in the IV Bu/Cy compared with Cy/TBI group (P = .003). Cumulative incidence of 2-year nonrelapse mortality (NRM; ± standard deviation [SD]) was 12% ± 1% in the IV Bu/Cy group and 15% ± 2% in the Cy/TBI group (P = .14), and 2-year relapse incidence (RI; ± SD) was 26% ± 3% and 21% ± 1%, respectively (P = .012). Leukemia-free survival (LFS) rate (± SD) was 61% ± 2% after IV Bu/Cy and 64% ± 2% after Cy/TBI (P = .27). In multivariable analysis, adjusting for differences between both groups, patients who received IV Bu/Cy had lower acute and chronic GVHD, higher RI, and a trend toward lower NRM. LFS was not statistically different between the two conditioning regimens.
This retrospective study shows that final outcomes after myeloablative conditioning using IV Bu/Cy were not statistically different from those after Cy/TBI.
Journal of Clinical Oncology 08/2013; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.Bone Marrow Transplantation advance online publication, 27 May 2013; doi:10.1038/bmt.2013.73.
Bone marrow transplantation 05/2013; · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Minor histocompatibility antigens (minor H antigens) are genetically polymorphic peptides that have been shown to elicit immune response when mismatched between donor and recipient of haematopoietic stem cell transplantation (HSCT). Depending on the expression profiles, mismatches in these genes may either lead to harmful graft-versus-host (GvH) reaction or desired graft-versus-leukaemia (GvL) effect. We analysed retrospectively the effect of HLA-restricted matching 11 established autosomal minor H antigens on the risk of graft-versus-host disease and relapse in 311 HLA-matched sibling HSCT of a single centre. Increased incidence of chronic GvH disease was shown to be associated with mismatches in the HA-8 and ACC-1. The mRNA expression profiles in a large set of healthy and malignant tissue samples of minor H antigen genes demonstrated in silico that the expression profiles of HA-8 and ACC-1 were surprisingly different: HA-8 gene was expressed in practically all tissues, whereas ACC-1 gene had a restricted profile. The results demonstrated that mismatches in minor H antigens HA-8 and ACC-1 predisposed to chronic graft-versus-host disease (GvHD).
International Journal of Immunogenetics 03/2013; · 1.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report the long-term results of a prospective randomized study on the use of ursodeoxycholic acid (UDCA) for prevention of hepatic complications after allogeneic stem cell transplantation. Two hundred forty-two patients, 232 with malignant disease, were randomized to receive (n = 123) or not to receive (n = 119) UDCA from the beginning of the conditioning until 90 days post-transplantation. The results were reported after 1-year follow-up. UDCA administration reduced significantly the proportion of patients developing high serum bilirubin levels as well as the incidence of severe acute graft-versus-host disease (GVHD), liver GVHD, and intestinal GVHD. In the UDCA prophylaxis group, nonrelapse mortality (NRM) was lower and overall survival better than in the control group. After a 10-year follow-up, the difference in the survival and NRM in favor of the UDCA-treated group, seen at 1 year, was maintained (survival 48% versus 38%, P = .037; NRM 28% versus 41%, P = .01). A landmark analysis in patients surviving at 1 year post-transplantation showed no significant differences between the study groups in the long-term follow-up in chronic GVHD, relapse rate, NRM, disease-free survival, or overall survival. These long-term results continue to support the useful role of UDCA in the prevention of transplant-related complications in allogeneic transplantation.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2013; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this multicenter retrospective study, the long-term outcomes of 878 adults with AML and refractory anemia with excess blasts (RAEB) with BM blasts <10% who underwent transplantation with an HLA-identical sibling donor between 1998 and 2004 were analyzed according to four regimens of conditioning intensity: reduced-intensity conditioning (RIC) (either intermediate RIC (IntermRIC) or non-myeloablative (NMA) RIC), and myeloablative conditioning (MC) in 718 patients (either conventional MC or hyperintense MC. In multivariate cox analysis, patients undergoing NMA transplantation had lower non-relapse mortality risk in the first 100 days after transplantation (P<0.01), but a higher risk beyond day +100 (P=0.02), as well as higher relapse incidence in the first 12 months (P<0.01), but the risk was similar in all groups beyond 12 months. The probabilities of PFS and OS up to 7 years were significantly lower only in the NMA subgroup (P0.01 for both). The 7-year OS was 53%, 29%, 56% and 51%, respectively. Our data suggest that prospective studies comparing RIC regimens (especially IntermRIC) with MC are appropriate in patients with AML and RAEB who are in a non-advanced disease status.Bone Marrow Transplantation advance online publication, 3 December 2012; doi:10.1038/bmt.2012.236.
Bone marrow transplantation 12/2012; · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peripheral blood used as a source of stem cells for transplantation (PBSCT) is known to exert stronger immune-mediated effects compared with BM (BMT). We decided to retrospectively analyze the impact of stem cell source on the OS of CML patients who relapsed after either matched related donor PBSCT (N=168) or BMT (N=216) and were treated with donor lymphocyte infusions (DLI). Univariate analysis revealed a lower probability of OS after DLI in patients relapsing after PBSCT vs BMT (66% vs 79% at 5 years, P=0.013). However, a multivariate Cox analysis did not reveal any significant impact of PBSCT as a risk factor for decreased OS for patients transplanted in first chronic phase (CP1; hazard ratio (HR) 1.036, 95% confidence interval (CI) 0.619-1.734). A statistical interaction term suggested that the impact of stem cell source on OS after DLI was different for those transplanted in advanced phases (negative impact of previous PBSCT-HR 2.176, 95% CI 0.930-5.091). In summary, the stem cell source does not affect the OS of CML patients who underwent PBSCT in CP1, relapsed and were treated with DLI. However, when the patients were transplanted in advanced phases, previous PBSCT seems to negatively affect OS after DLI compared with BMT.Bone Marrow Transplantation advance online publication, 26 November 2012; doi:10.1038/bmt.2012.234.
Bone marrow transplantation 11/2012; · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment algorithms for poor cytogenetic-risk myelodysplastic syndrome (MDS), defined by chromosome 7 abnormalities or complex karyotype (CK), include allogeneic stem cell transplantation (alloSCT). We studied outcome of alloSCT in chromosome 7 abnormal MDS patients as this data are scarce in literature. We specifically focused on the impact of the extra presence of CK and monosomal karyotype (MK). The European Group for Blood and Marrow Transplantation database contained data on 277 adult MDS patients with a chromosome 7 abnormality treated with alloSCT. Median age at alloSCT was 45 years. Median follow-up of patients alive was 5 years. Five-year progression-free survival (PFS) and overall survival (OS) were 22% and 28%, respectively. In multivariate analysis, statistically significant predictors for worse PFS were higher MDS stages treated, but not in complete remission (CR) (hazards ratio (HR) 1.7), and the presence of CK (HR 1.5) or MK (HR 1.8). Negative predictive factors for OS were higher MDS stages treated, but not in CR (HR 1.8), and the presence of CK (HR 1.6) or MK (HR 1.7). By means of the cross-validated log partial likelihood, MK showed to have a better predictive value than CK. The results are relevant when considering alloSCT for higher-stage MDS patients having MK including a chromosome 7 abnormality.Leukemia advance online publication, 20 November 2012; doi:10.1038/leu.2012.297.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2012; · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated whether a young human leukocyte antigen (HLA)-matched unrelated donor (MUD) should be preferred as donor to an HLA-identical sibling (MRD) for older patients with myelodysplastic syndrome (MDS) (50 years) who underwent allogeneic stem cell transplantation (AHSCT). Outcomes of 719 MDS patients with a median age of 58 years (range, 50-73 years) who received AHSCT from related (n=555) or unrelated (n=164) donors between 1999 and 2008 and reported to the European Group for Blood and Marrow Transplantation were analyzed. The median donor age of the MRD was 56 years (range: 35-78), in contrast to 34 years (range: 19-64) for the MUDs. Influence of donor's age on survival was not observed for MRD (hazard ratio (HR): 1.01 (95% confidence interval (CI): 0.99-1.02), P=0.2), but there was a significant impact of MUD's age on outcome (HR: 1.03 (95% CI: 1.01-1.06); P=0.02). Transplantation from younger MUDs (<30 years) had a significant improved 5-year overall survival in comparison with MRD and older MUDs (>30 years): 40% vs 33% vs 24% (P=0.04). In a multivariate analysis, AHSCT from young MUD (<30 years) remained a significant factor for improved survival in comparison with MRD (HR: 0.65 (95% CI: 0.45-0.95), P=0.03), which should be considered in donor selection for older patients.Leukemia advance online publication, 21 August 2012; doi:10.1038/leu.2012.210.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2012; · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several prognostic factors for the outcome after allogeneic hematopoietic stem-cell transplant (HSCT) from matched unrelated donors have been postulated from registry data; however, data from randomized trials are lacking. We present analyses on the effects of patient-related, donor-related, and treatment-related prognostic factors on acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) in a randomized, multicenter, open-label, phase III trial comparing standard graft-versus-host-disease (GVHD) prophylaxis with and without pretransplantation ATG-Fresenius (ATG-F) in 201 adult patients receiving myeloablative conditioning before HSCT from HLA-A, HLA-B antigen, HLA-DRB1, HLA-DQB1 allele matched unrelated donors. High-resolution testing (allele) of HLA-A, HLA-B, and HLA-C were obtained after study closure, and the impact of an HLA 10/10 4-digit mismatch on outcome and on the treatment effect of ATG-F versus control investigated. Advanced disease was a negative factor for relapse, DFS, and OS. Donor age ≥40 adversely affected the risk of aGVHD III-IV, extensive cGVHD, and OS. Younger donors are to be preferred in unrelated donor transplantation. Advanced disease patients need special precautions to improve outcome. The degree of mismatch had no major influence on the positive effect of ATG-F on the reduction of aGVHD and cGVHD.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 06/2012; 18(11):1716-26. · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Graft-versus-host disease (GvHD) is a major complication in hematopoietic stem cell transplantation (HSCT). The immune response against gut microbes is thought to be an important factor in the beginning of GvHD. Toll-like receptors (TLR) recognize molecular structures of microbes and viruses and play central part in the innate immunity. We studied whether genetic variation in the TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 genes confers susceptibility to GvHD in 305 human leucocyte antigen-identical sibling donor HSCT's performed in a single Finnish centre. The results showed that the genetic markers rs4833079 (P = 0.035) in TLR1, rs4837656 (P = 0.032) and rs17582214 (P = 0.029) in TLR4, rs10737416 (P = 0.048) in TLR5, rs6531656 (P = 0.035) in TLR6, and rs337629 (P = 0.005) in TLR10 were associated with the occurrence of acute GvHD. Interestingly, two markers in the TLR5 gene, rs2800230 (P = 0.010) and rs2800237 (P = 0.017), were associated with chronic GvHD. These results indicate that many genes of the TLR system are involved in the overall genetic risk for GvHD and emphasize the role of innate immunity in GvHD.
Scandinavian Journal of Immunology 06/2012; 76(3):336-41. · 2.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ringdén O, Labopin M, Beelen DW, Volin L, Ehninger G, Finke J, Greinix HT, Kyrcz-Krzemien S, Bunjes D, Brinch L, Niederwieser D, Arnold R, Mohty M, Rocha V, for the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) (Karolinska University Hospital Huddinge, Sweden; CEREST-TC EBMT, Paris, France; University of Duisburg-Essen, Germany; Helsinki University Central Hospital, Helsinki, Finland; University Hospital, Dresden, Germany; University Hospital, Freiburg, Germany; Medical University Vienna, Vienna, Austria; Medical University of Silesia, Katowice, Poland; University Hospital, Ulm, Germany; Rikshospitalet, Oslo, Norway; University Hospital, Leipzig, Germany; Charité University Hospital, Berlin, Germany; Université de Nantes, Nantes, France; and Hôpital Saint-Louis, Paris, France). Bone marrow or peripheral blood stem cell transplantation from unrelated donors in adult patients with acute myeloid leukaemia, an Acute Leukaemia Working Party analysis in 2262 patients. J Intern Med 2012; 272: 472-483. Background. No survival benefit of using blood stem cells instead of bone marrow (BM) has been shown in matched unrelated donor (MUD) transplantation. Design and methods. In a retrospective registry analysis, we compared the use of blood stem cells (n = 1502) and BM (n = 760) from unrelated donors in patients aged 18-60 years with acute myeloid leukaemia (AML) undergoing myeloablative conditioning between 1997 and 2008. The blood stem cell recipients were older (P < 0.01), had more advanced disease (P < 0.0001) and received less total body irradiation (P < 0.0001) and more antithymocyte globulin (P = 0.01). Results. Recovery of neutrophils and platelets was faster with blood stem cells (P < 0.0001). The incidence of acute graft-versus-host disease (GVHD) was similar, but there was more chronic GVHD in the blood stem cell group [hazard ratio (HR) = 1.29, P = 0.02]. There were no significant differences in nonrelapse mortality (NRM), relapse incidence and leukaemia-free survival (LFS) between the two groups amongst patients with AML in remission. In patients with advanced leukaemia, NRM was lower (HR = 0.61, P = 0.02) and LFS was prolonged (HR = 0.67, P = 0.002) when blood stem cells were used. At 3 years, LFS for all patients, regardless of remission status, was 41% for both treatment groups. The outcome was not affected after multivariable analysis adjusted for confounders. Conclusion. Blood stem cells compared with BM in MUD transplantation for patients with AML in remission resulted in the same rates of LFS. In patients with advanced leukaemia, the blood stem cell group had reduced NRM and improved LFS.
Journal of Internal Medicine 04/2012; 272(5):472-483. · 6.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with acute myeloid leukemia (AML) and FLT3/internal tandem duplication (FLT3/ITD) have poor prognosis if treated with chemotherapy only. Whether this alteration also affects outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) remains uncertain.
We analyzed 206 patients who underwent HLA-identical sibling and matched unrelated HSCTs reported to the European Group for Blood and Marrow Transplantation with a diagnosis of AML with normal cytogenetics and data on FLT3/ITD (present: n = 120, 58%; absent: n = 86, 42%). Transplantations were performed in first complete remission (CR) after myeloablative conditioning.
Compared with FLT3/ITD-negative patients, FLT3/ITD-positive patients had higher median leukocyte count at diagnosis (59 v 21 × 10(9)/L; P < .001) and shorter interval from CR to transplantation (87 v 99 days; P = .04). Other characteristics were similar in the two groups. At 2 years, relapse incidence (RI; ± standard deviation) was higher (30% ± 5% v 16% ± 5%; P = .006) and leukemia-free survival (LFS) lower (58% ± 5% v 71% ± 6%; P = .04) in FLT3/ITD-positive compared with FLT3/ITD-negative patients. In multivariate analyses, FLT3/ITD led to increased RI (hazard ratio [HR], 3.4; 95% CI, 1.46 to 7.94; P = .005), as did older age, female sex, shorter interval between CR and transplantation, and higher number of chemotherapy courses before achieving CR. FLT3/ITD positivity was associated with decreased LFS (HR, 0.37; 95% CI, 0.19 to 0.73; P = .002), along with older age and higher number of chemotherapy courses before achieving CR.
FLT3/ITD adversely affected the outcome of HSCT in the same direction it does after chemotherapy; despite this, more than half of the patients harboring this mutation who received transplants were alive and leukemia free at 2 years. To further improve the results, use of FLT3 inhibitors before or after HSCT deserves investigation.
Journal of Clinical Oncology 03/2012; 30(7):735-41. · 18.04 Impact Factor