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We aimed to evaluate the determinants of survival in myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) and to describe factors predicting the main post-HCT complications. This retrospective study by the European Society for Blood and Marrow Transplantation included 2916 myelofibrosis patients who underwent first allo-HCT from an HLA-identical sibling or unrelated donor between 2000 and 2016. After a median follow-up of 4.7 years from transplant, projected median survival of the series was 5.3 years. Factors independently associated with increased mortality were age ≥ 60 years and Karnofsky Performance Status

Background. Use of haploidentical cell transplantation (Haplo-HCT) with peripheral blood stem cells (PBSC) is increasing for acute myeloid leukemia (AML). We explored whether the addition of antithymocyte globulin (ATG) to post-transplant cyclophosphamide (PTCy) allows better outcomes than PTCy alone in Haplo-PBSC.Methods. We included 441 adult patients undergoing a first Haplo-PBSC for AML in first or second complete remission; graft-versus-host disease (GVHD) prophylaxis contained either PTCy alone (n = 374) or ATG + PTCy (n = 67), in addition to cyclosporine A (CsA) and mycophenolate mofetil (MMF) as other immunosuppressive agents. Transplant period was 2011–2019.Results. No major imbalances were observed between the two groups. Median age was 56 years and median year of Haplo-HCT was 2017 for both groups. Most patients received a reduced-intensity conditioning regimen (57% and 61% in PTCy and ATG + PTCy, respectively; p = 0.54). Median follow-up was 19 versus 15 months in PTCy and ATG + PTCy, respectively (p = 0.59). Neutrophil engraftment occurred in 97% and 98% of PTCy and ATG + PTCy, respectively. In univariate analysis, no statistical differences in transplant outcomes were observed between PTCy and ATG + PTCy. In multivariate analysis ATG + PTCy resulted in a lower risk of chronic GVHD as compared to PTCy alone (HR = 0.46, 95% CI 0.23–0.93; p = 0.03). No differences were observed for the other transplant outcomes.Conclusion. In Haplo-PBSC, addition of ATG to PTCy (with CsA and MMF) is feasible, better at preventing chronic GVHD, and survival and transplant outcomes are comparable to those with PTCy alone, without increasing transplant toxicity, mortality, or relapse incidence.

Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients without an HLA-identical donor, haploidentical (haplo-) HCT is becoming the leading source of stem cell donation. However, data are scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age, 31 years; range, 18 to 68 years) with T-ALL who underwent haplo-HCT with post-transplantation cyclophosphamide (ptCy) between 2010 and 2017. The median duration of follow-up of living patients was 23 months. The 2-year incidences of relapse and nonrelapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS), and graft-versus-host disease, relapse-free survival (GRFS) were 34%, 42%, and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplantation, being 49% and 55%, respectively, for patients in first complete remission (CR1); 34% and 50%, respectively, for those in second CR (CR2); and 8% and 12%, respectively, for patients with active disease. On multivariate analysis, only disease status was found to affect LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at the time of haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in patients in CR. Despite the limitation of the small sample size, our results were not affected by the type of conditioning, calling into question the need for total body irradiation-based myeloablative conditioning in that setting.

International audience; Whether to choose Haploidentical (Haplo) or one-antigen mismatched unrelated donor (1Ag-MMUD) hematopoietic cell transplantation (HCT) with post-transplant cyclophosphamide (PTCy) remains an unanswered question. We compared PTCy- Haplo-HCT to PTCy-1Ag-MMUD-HCT for acute myeloid leukemia (AML) in complete remission (three groups: 1Ag-MMUD using peripheral blood (1Ag-MMUD-PB; n = 155); Haplo using bone marrow (Haplo-BM; n = 647) or peripheral blood (Haplo-PB; n = 949)). Haplo-BM and Haplo-PB had a higher non-relapse mortality (NRM) compared to 1Ag-MMUD-PB (HR 2.28, 95% CI 1.23-4.24, p

The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with peripheral blood stem cells (PBSCs) to treat acute myelogenous leukemia (AML) is increasing. We explored whether the addition of antithymocyte globulin (ATG) to post-transplantation cyclophosphamide (PTCy) allows better outcomes compared with PTCy alone in haplo-HCT with PBSCs (haplo-PBSCT). We included 441 adult patients undergoing a first haplo-PBSCT for AML in first or second complete remission; graft-versus-host disease (GVHD) prophylaxis contained either PTCy alone (n = 374) or ATG plus PTCy (n = 67), in addition to cyclosporine A (CsA) and mycophenolate mofetil (MMF) as other immunosuppressive agents. All transplantations were performed between 2011 and 2019. No major imbalances were observed between the 2 groups. For both groups, the median patient age was 56 years, and the median year of haplo-PBSCT was 2017. Most patients received a reduced-intensity conditioning regimen (57% in the PTCy group and 61% in the ATG+PTCy group; P = .54). The median follow-up was 19 months in the PTCy group versus 15 months in the ATG+PTCy group (P = .59), and the rate of neutrophil engraftment in the 2 groups was 97% and 98%, respectively. In univariate analysis, there were no statistical differences in transplantation outcomes between the 2 groups. In multivariate analysis, ATG+PTCy was associated with a lower risk of chronic GVHD compared with PTCy alone (hazard ratio, .46; 95% confidence interval, .23 to .93; P = .03). No between-group differences in the other transplantation outcomes were seen. In haplo-PBSCT, the addition of ATG to PTCy (with CsA and MMF) is feasible and better at preventing chronic GVHD and is associated with survival and transplantation outcomes comparable to those with PTCy alone, without increasing transplantation toxicity, mortality, or relapse incidence.

Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.

Introduction Survival rate of patients with chemorefractory acute myeloid leukemia (AML) or myelodysplastic syndrome with excess blasts (MDS-EB) is poor. Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy in these patients. Patients and Methods We report a retrospective analysis of outcomes of therapy of 24 patients with AML or MDS-EB refractory to high-dose salvage chemotherapy or who had failed previous HCT, who received T-cell–replete HLA haploidentical HCT in aplasia after cladribine/cytarabine-based chemotherapy followed by reduced intensity or myeloablative conditioning. All patients had active disease before commencement of the treatment. Results Of the patients, 91.7% achieved complete remission (CR), whereas 2 patients (8.2%) died in aplasia. One-year relapse rate was 49.3%. Cumulative incidence of nonrelapse mortality (NRM) was 25.6%. In a subgroup of patients with HCT–comorbidity index score ≤ 3, NRM was 15.4%. Two-year overall survival and relapse-free survival were 30.6% and 22.6%, respectively. Incidence of grade 3 and 4 acute graft versus host disease was 21.3% and 8.3, respectively. Conclusion We found that sequential therapy with HCT in aplasia after cladribine/cytarabine chemotherapy is feasible, results in high CR rates, and has acceptable toxicity profile; however, posttransplant relapse is common in patients treated with active disease.

The causes and rates of late patient-mortality following alloHCT for myelodysplastic syndromes or secondary acute myeloid leukemia were studied, to assess the contribution of relapse-related, treatment-related, and population factors. Data from EBMT on 6434 adults, who received a first alloHCT from January 2000 to December 2012, were retrospectively studied using combined land-marking, relative-survival methods and multi-state modeling techniques. Median age at alloHCT increased from 49 to 58 years, and the number of patients aged ≥65 years at alloHCT increased from 5 to 17%. Overall survival probability was 53% at 2 years and 35% at 10 years post-alloHCT. Survival probability at 5 years from the 2-year landmark was 88% for patients

Measurable residual disease (MRD) prior to hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) in first complete morphological remission (CR1) is an independent predictor of outcome, but few studies address CR2. This analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation registry assessed HCT outcomes by declared MRD status in a cohort of 1042 adult patients with AML CR2 at HCT. Patients were transplanted 2006–2016 from human leukocyte antigen (HLA) matched siblings (n = 719) or HLA 10/10 matched unrelated donors (n = 293). Conditioning was myeloablative (n = 610) or reduced-intensity (n = 432) and 566 patients (54%) had in-vivo T cell depletion. At HCT, 749 patients (72%) were MRD negative (MRD NEG) and 293 (28%) were MRD positive (MRD POS). Time from diagnosis to HCT was longer in MRD NEG than MRD POS patients (18 vs. 16 months (P P P = 0.001), but there was no difference in terms of overall survival. Prognostic factors for relapse and LFS were MRD NEG status, good risk cytogenetics, and longer time from diagnosis to HCT. In-vivo T cell depletion predicted relapse.

The timing of immunosuppressive therapy used in combination with post-transplantation cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (haplo-HSCT) is not standardized. We evaluated the schedules of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on days +3 and +4 along with tacrolimus (group 1; n = 215), with cyclosporine A (CSA) and mycophenolate mofetil (MMF) from day +5 (group 2; n = 170), or CSA + MMF from day 0 or 1 with PTCY on days +3 and +5 (group 3; n = 124). Compared with the other 2 groups, patients in group 3 were younger (median age, 46 years; P = .02) and more often received bone marrow (77%; P < .01) and a regimen containing thiotepa, fludarabine, and busulfan (84%; P< .01). At 2 years, overall survival was 44% was in group 1, 48% in group 2, and 59% in group 3 (P= .15); leukemia-free survival (LFS) was 43%, 46%, and 53% (P= .05); and refined graft-versus-host disease-free, relapse-free survival (rGRFS) was 33%, 39%, and 36% (P = .02). The incidence of grade II-IV acute GVHD was 25% in group 1, 39% in group 2, and 18% in group 3 (P< .01); incidence of chronic GVHD was 25%, 21%, and 24% (P= .50); relapse incidence was 36%, 37%, and 26% (P= .02); and nonrelapse mortality was 26%, 20%, and 21% (P= .35). On multivariate analysis, early start of immunosuppression therapy at day +1 followed by PTCY was associated with a better LFS (hazard ratio [HR],. 58; P= .02) and improved rGRFS (HR,. 62; P = .02). In this study, the timing of immunosuppression influenced the outcomes of haplo-HSCT with PTCY. An early start of CSA + MMF with PTCY administered on days +3 and +5 improves LFS and rGRFS.

Introduction. In the absence of an HLA-identical sibling or a matched unrelated donor, whether to prefer a Haploidentical (Haplo) or a one antigen mismatched unrelated donor (MMUD) for allogeneic hematopoietic cell transplantation (HCT) remains an unanswered question. Implementation of graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) was initially pioneered in the Haplo and then also extended to MMUD setting, resulting in low rates of GVHD. Methods. This was a retrospective study from the EBMT registry. Included were adults undergoing either Haplo- or MMUD-HCT for acute myeloid leukemia during the period 2010-2018 and who were in first or second complete remission at allo-HCT. Only patients receiving unmanipulated grafts with PTCY as GVHD prophylaxis were included. Ex vivo and in vivo T-cell depletion were exclusion criteria. Comparisons were made among three groups: MMUD-HCT with peripheral blood as stem cell source (PBSC; n=124); Haplo-HCT with bone marrow (Haplo-BM; n=560); Haplo-HCT with PBSC (Haplo-PB; n=769). Results. Patients in Haplo-PB were older (median age of 55 years versus (vs) 52 and 51 years in MMUD-HCT and Haplo-BM, respectively; p Conclusion. According to our results, use of MMUD is associated to significantly higher LFS. However, our results highlight that both MMUD- and Haplo-HCT are valid options for transplant candidates, with no differences in GRFS. On the other hand, when choosing Haplo over MMUD, one should consider BM as stem cell source in order to better prevent GVHD. Further strategies to better prevent NRM are needed, particularly in Haplo-HCT. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise:Jazz Pharmaceuticals: Honoraria. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Pane:Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Aim: Dynamic assessment of trends over time in patient- and transplant-specific characteristics and outcomes for patients undergoing 1st allogeneic haematopoietic cell transplant (allo-HCT) for Myelofibrosis (MF). Methods and Results: A total of 4142 MF patients were analysed who underwent allo-HCT between 1995-2018 (24-year period) across 278 centres based on data reported to the European Society for Blood and Marrow Transplantation. For analysis, 4 cohorts were considered based on year of allo-HCT: 60 years accounted for 8.7% of adults undergoing allo-HCT whereas for 2015-2018 this was 47%. Over time, increasing number of patients with a Karnofsky performance status (KPS) Conclusions: Despite a marked increase over this 24-year period in recipient age, RIC regimen utilisation and use of both URD and MMRD, this comprehensive analysis demonstrates stable OS and EFS rates. However, rates of GVHD have decreased over time, in particular extensive cGVHD. Further work is required to improve both the considerable NRM and relapse rates which remain significant. Disclosures McLornan: JAZZ PHARMA: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau; NOVARTIS: Honoraria, Speakers Bureau. Platzbecker:Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Chevallier:Incyte Corporation: Honoraria. Martínez-Lopez:Altum, Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Vivia Biotech: Honoraria; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding. Yakoub-Agha:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria.

Contains fulltext : 202803.pdf (Publisher’s version ) (Open Access) This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34(+) cell dose was 4.8x10(6)/kg (range, 1.7 to 22.9; n=43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28days was 82% (range, 70% to 93%), at a median of 21days (range, 19 to 23). At 2years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion.

This retrospective study by the European Society for Blood and Marrow Transplantation analyzed the outcome of 2224 patients with myelofibrosis (MF) who underwent allogeneic stem cell transplantation (allo-SCT) between 2000 and 2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced-intensity conditioning (RIC). Median patient age was 52.9 years (range, 18 to 74 years) and 57.5 years (range, 21 to 76 years) in the MAC and RIC cohorts, respectively. Donor type was similar: matched sibling donors (MAC, 317 [41%]; RIC, 552 [38%]) and unrelated donors (MAC, 464 [59%]; RIC, 891 [62%]). Median time to both neutrophil and platelet (>20 × 109/L) engraftment did not differ between cohorts. Rates of grade II to IV acute GVHD were 28% (MAC) and 31% (RIC; P = NS). Cumulative chronic GVHD rates (limited/extensive) were 22%/27% (MAC) and 19%/31% (RIC; P = .10). Cumulative incidences of nonrelapse 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), respectively. There was a trend toward a higher relapse rate with RIC regimens compared with MAC (P = .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 5-year probabilities of overall survival (OS) was noted: MAC (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and RIC (51.0%; 95% CI, 48.3% to 53.7%); P = .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% to 36.1%) in the MAC group and 26.1% (95% CI, 23.9% to 28.2%) in the RIC group (P = .001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 years), using an unrelated donor and a Karnofsky Performance Status of 80 or less. For the RIC cohort, worse OS and NRM were associated with age 60 to 70 years compared with 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 toward 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 optimization to reduce significant relapse and NRM rates is required.

The use of anti-thymocyte globulin (ATG) has represented the standard of care in graft-versus-host disease (GVHD) prophylaxis in patients undergoing a mismatched unrelated donor (MMUD) transplant. The safety and feasibility of posttransplant cyclophosphamide (PTCY) in this setting have been reported recently, but no study has compared the outcomes of PTCY vs ATG in 9/10 MMUD transplants. Using the registry data of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we performed a matched-pair analysis comparing those 2 strategies in a 9/10 MMUD setting. Ninety-three patients receiving PTCY were matched with 179 patients receiving ATG. A significantly lower incidence of severe acute GVHD was observed with PTCY compared with ATG. Recipients of the former also showed higher leukemia-free survival and GVHD/relapse-free survival (GRFS). When performing a subgroup analysis including patients receiving peripheral blood stem cells, being in complete remission, or receiving the same associated immunosuppressive agents, superiority of PTCY over ATG was confirmed. Similar to the haploidentical setting, use of PTCY is an effective anti-GVHD prophylaxis in the 9/10 MMUD transplant. Use of PTCY may also provide better outcomes in long-term disease control. These results need confirmation in large prospective randomized trials.

Allogeneic Haematopoietic Stem Cell Transplant (allo-HSCT) remains the only curative approach for Myelofibrosis (MF). Scarce information exists in the literature on the outcome and, indeed, management of those MF patients who relapse following transplant. We hereby report on the management and outcome of 202 patients who relapsed post allo-HSCT for MF.

International audience; Acute myeloid leukemia (AML) patients harboring the FLT3-ITD mutation are considered a high risk patient subset preferentially allocated for allogeneic stem cell transplantation in first remission. Whether FLT3-ITD retains a prognostic role in haploidentical stem cell transplantation (haplo-SCT) is unknown. To analyze the prognostic impact of FLT3-ITD in haplo-SCT, we performed a retrospective analysis of the multicenter registry of the acute leukemia working party of the European Society for Blood and Marrow Transplantation. We included all adult AML patients with known FLT3 status who underwent a first T-cell replete related haplo-HCT in first complete remission from 2005 to 2016. We evaluated 293 patients of whom 202 were FLT3wt and 91 were FLT3-ITD mutated. FLT3-ITD patients were more likely to be NPM1 mutated as well as be in the intermediate risk cytogenetic risk category. In multivariate analysis, patients with FLT3-ITD had comparable rates of relapse incidence [ Hazard ratio (HR) 51.34, confidence interval (CI) 95%, 0.67-2.7; P=.9] and leukemia-free survival (HR=.99, CI 95%, 0.62-1.57; P=.9) to those of FLT3(wt) patients. Overall survival, the incidence of nonrelapse mortality, and graft versus host disease-free/relapse-free survival were not significantly impacted by FLT3-ITD status. Furthermore, relapse and overall survival were comparable between FLT3-ITD patients transplanted from various donor pools, namely matched siblings, unrelated donors, haplo-SCT). Finally, subset analysis of patients with intermediate risk cytogenetics confirmed the absence of a prognostic impact of FLT3-ITD also for this patient segment. In AML patients undergoing T-cell replete haplo-SCT, the FLT3-ITD mutation possibly does not retain its prognostic significance.

Background Primary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML. Methods The current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors (n = 660) versus unrelated donors (n = 381), for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant ≥90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality. Conclusions HSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients’ outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0498-8) contains supplementary material, which is available to authorized users.

Item does not contain fulltext We report a retrospective analysis of 246 myelodysplastic syndrome (MDS) patients in the EBMT (The European Society for Blood and Marrow Transplantation) database who were transplanted for International Prognostic Scoring System (IPSS) low or intermediate-1 disease. The majority of these patients (76%) were reclassified as intermediate or higher risk according to R-IPSS. The 3-year overall survival (OS) and PFS were 58% and 54%, respectively. In a multivariate analysis, adverse risk factors for PFS were marrow blast percentage (hazard ratio (HR): 1.77, P=0.037), donor/recipient CMV serostatus (donor-/recipient+: HR: 2.02, P=0.011) and source of stem cells (marrow and non-CR: HR: 5.72, P

Contains fulltext : 171274.pdf (Publisher’s version ) (Open Access) Many pre-transplant factors are known to influence the outcome of allogeneic stem cell transplantation (SCT) treatment in myelodysplastic syndromes (MDS). However, patient cohorts are often heterogeneous by disease stage and treatment modalities, which complicates interpretation of the results. This study aimed to obtain a homogeneous patient cohort by including only de novo MDS patients who received upfront allogeneic SCT after standard high dose myelo-ablative conditioning. The effect of pre-transplant factors such as age, disease stage, transfusions, iron parameters and comorbidity on overall survival (OS), non-relapse mortality (NRM), and relapse incidence (RI) was evaluated in 201 patients. In this cohort, characterized by low comorbidity and a short interval between diagnosis and transplantation, NRM was the most determinant factor for survival after SCT (47 % after 2-year follow-up). WHO classification and transfusion burden were the only modalities with a significant impact on overall survival after SCT. Estimated hazard ratios (HR) showed a strongly increased risk of death, NRM and RI, in patients with a high transfusion-burden (HR 1.99; P = 0.006, HR of 1.89; P = 0.03 and HR 2.67; P = 0.03). The HR's for ferritin level and comorbidity were not significantly increased.

AIM OF THE STUDY, PATIENTS AND METHODS : The data obtained from a long-term follow-up for a period of 30 years (1988-2017) were analyzed in a group of 529 patients with primary MDS and factors affecting prolonged survival were detected using different statistical methods including Kaplan Maier test and multivariate analysis. RESULTS : The results confirmed usefulness of both IPSS and IPSS-R (median survival in months for risk groups : very low - 73.7, low - 40.0, intermediate - 27.0, high - 9.0, very high - 3.5). In a subgroup of 249 patients with less advanced disease without excess of blasts, allogeneic SCT represented the most favouring treatment approach leading to estimated 10 years survival in 49.1% of patients. However, when compared to patients treated by supportive care only, a benefit in overall survival for SCT did not become significant before 5 years of follow-up (estimated 5 years survival /e5yS/: 43.3% for supportive care vs. 54.7 % for SCT). Only 2 (3.8%) out of 53 transplanted patients died later than after 5 years follow-up in comparison to 31 (20.8%) out of 149 patients on supportive care; 22 of them died on complications not directly related to MDS and a late disease progression (between 6 and 26 years after diagnosis of MDS) was observed in 9 patients. Transplantation related mortality was 30.2%, SCT at the time of disease progression (>5% of bone marrow /BM/ blasts) and prolonged (>3 months) administration of corticosteroids prior to SCT were independent adverse prognostic factors for SCT outcome (P CONCLUSIONS : The analysis of long-term follow-up showed that younger patients with less advanced MDS without excess of blasts and adverse prognostic factors should be transplanted as soon as possible after diagnosis before disease progression. An advantage of more conservative approach to patients with early disease who are not indicated for SCT was confirmed by presence of a relatively high number of patients surviving 5 years with supportive care only. SCT represented the treatment of choice for advanced MDS and reduction of BM blasts prior to SCT siginficantly affected outcome of SCT. Administration of HMA significantly improved short term survival but did not affect long term outcome of patients. Disclosures No relevant conflicts of interest to declare.

Background: PRF-AML is associated with a dismal prognosis. Approximately one third of patients younger than 60 years, and 50 % of older patients, with newly diagnosed AML, fail to achieve complete remission (CR) with standard induction chemotherapy. Allo-SCT in the setting of active disease is an alternative strategy. The increased availability of unrelated donors (UD) together with the use of reduced-intensity conditioning (RIC) regimens have opened the possibility for transplantation to a larger number of patients in comparison to standard myeloablative regimens (MAC). Because of the high risk of allo-SCT in this setting, there are still questions on the patient outcome depending on the donor type. Aims: The current study aimed to compare the outcomes of allo-SCT from matched sibling donors (MSD) (n=660) vs UDs (n=381), for patients with PRF AML. Methods: The major endpoints were to assess overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and non relapse mortality (NRM). Results: 660 patients received a MSD, 296 patients a matched UD (10/10) and 85 a mismatched UD (9/10), respectively. Median age was higher in the UD group (50.5 yrs (18-74) vs 47.7 yrs (18-74), p=0.006). The median time from diagnosis to allo-SCT was similar (110 days [60-180] in the MSD group vs 111days [60-178] in the UD group; p=0.33). In the MSD allo-SCT, 57 % received a MAC regimen, 29% a RIC regimen, and 14% a sequential conditioning regimen; while, in the UD transplants, 44.4 % received a MAC regimen, 24.4% a RIC regimen, and 31.2% a sequential conditioning regimen (p50 yrs, cytogenetics, time from diagnosis to transplant and CMV positive status whereas Karnofsky status at transplant ≥90% (KS) was associated with better OS. 71% patients with a MSD and 68.6% patents with an UD reached CR after allo-SCT (p=0.73). In univariate analysis, RI at 2 years was 53.7% in MSD group and 56.4% in UD group, respectively (p=0.038). In multivariate analysis for RI, cytogenetics and time from diagnosis to transplant were the only risk factors associated with increased relapse [(HR=1.74, 95%CI,1.30-2.33, p=0.0002) (HR=1.29, 95%CI,1.06-1.58, p=0.01), respectively] whereas KS was a protective factor (HR=0.77, 95%CI,0.62-0.95, p=0.01). The incidence of aGVHD≥2 was higher in UD group (35.5% vs 27.9%, p=0.012). At 2 years, the cumulative incidence of chronic GVHD (cGVHD) was not statistically different between MSD and UD (28.9% and 25.8%, respectively, p=0.56) (univariate analysis). As for, NRM at 2 years, there was not statistical difference between MSD and UD groups (21% vs 25.1%, p=0.112). In multivariate analysis, patient age (>50 yrs) and CMV positive status were factors associated with higher NRM (HR=1.77, 95%CI, 1.27-2.47, p=0.001; HR=1.68, 95%CI, 1.14-2.47, p=0.008), while RIC regimen compared to MAC regimen was the only factor associated with lower NRM (HR=0.59, 95%CI, 0.41-0.85, p=0.005). Conclusion Allo-SCT may rescue one third of patients with primary refractory AML. Importantly, the donor type did not have any impact on PRF patients' outcomes. In contrast, time to transplant was a major prognostic factor for LFS and OS. For patients with PRF AML, that do not have a matched sibling donor, allo-HST from UD is a suitable option and thus initiation of an early search and allocating of a suitable donor is therefore indicated. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Finke: Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Mohty:Janssen: Honoraria; Celgene: Honoraria.

Development of highly sensitive quantitative assays for cytomegalovirus (CMV) DNA detection is crucial for identification of immunodeficient patients at high risk of CMV disease. We designed 2 internally controlled competitive quantitative assays, enzyme-linked immunosorbent assay (ELISA)-based and real-time polymerase chain reaction (PCR) tests, using amplification of the same segment of the CMV genome. The aim of this study was to compare sensitivity, specificity, and laboratory performance characteristics of these assays. In both assays, a 159-bp segment of UL83 gene was amplified. External and internal controls were constructed by cloning the amplification product and heterogenous DNA segment flanked by target sequences for CMV-derived primers into bacterial plasmids, respectively. Real-time PCR was performed on LightCycler (Roche Diagnostics, Mannheim, Germany), and amplicons were detected using fluorescence resonance energy transfer probes. Alternatively, PCR products were labeled by digoxigenin, hybridized to immobilized probes, and detected by ELISA. The assays were tested on genomic DNA isolated from laboratory strains of CMV, QCMD control panel, and CMV DNA-positive peripheral blood DNA samples from hematopoietic stem cell transplant recipients, previously characterized by pp65 antigenemia and qualitative nested PCR. Real-time and ELISA-based PCR assays showed a linear course of 1–10 8 and 10–10 5 copies of CMV DNA per reaction, respectively. When compared with ELISA-based PCR, real-time PCR showed superiority in inter- and intra-assay reproducibility. Both assays were highly specific in detecting CMV DNA. No difference in amplification efficiency of internal or external standards and wild-type CMV DNA was found. The assays exhibited 83% concordance in CMV DNA detection from clinical samples, all discrepant samples having low CMV DNA copy numbers. There was a good correlation between viral DNA loads measured by the 2 assays. Statistically significant correlation was observed between the numbers of CMV DNA copies and pp65-positive leukocytes in the samples tested. Both variants of competitive PCR are adequately sensitive to be used for CMV DNA quantitation in clinical samples. LightCycler PCR, having superior performance characteristics and being less time-consuming, seems to be more suitable for routine diagnosis.

This study reports outcomes of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning (RIC) in 186 patients with chronic myeloid leukemia (CML) from the European Group for Blood and Marrow Transplantation (EBMT). The median age was 50 years, and 64% were in first chronic phase (CP1), CP2 13%, accelerated phase 17%, and blast crises 6%. The median EBMT transplant score was 3. The day 100 transplantation-related mortality (TRM) was 6.1% (confidence interval [CI], 3.4%-11%) but rose to 23.3% (CI, 14%-27%) at 2 years. Fludarabine, busulfan, and antithymocyte globulin (Fd/Bu/ATG) was associated with the lowest TRM of 11.6% (CI, 4.7%-11%) at 1 year. Acute graft-versus-host disease (GvHD) grade II to IV occurred in 32% and chronic GvHD in 43% (extensive in 24%). ATG was associated with a lower incidence of chronic GvHD (cGvHD). The overall survival (OS) and progression-free survival (PFS) at 3 years were 58% (CI, 50%-66%) and 37% (CI, 30%-45%), respectively. Adverse OS was associated with advanced disease (relative risk [RR], 3.4). PFS was inferior in advanced disease (RR, 2.7) and a trend to improved outcomes with Fd/Bu/ATG (RR, 0.58). RIC allografts are feasible in CML in first or second CP. Since no other RIC regimen demonstrated superiority, Fd/Bu/ATG should be considered as baseline in future prospective trials.

The Infectious Diseases Working Party of the European Blood and Marrow Transplant Group conducted a survey to obtain information about the frequency, presentation, and treatment of mycobacterial infection (MBI) in stem cell transplant (SCT) recipients. Among 29 centers, MBI was diagnosed in 0.79% of 1513 allogeneic and 0.23% of 3012 autologous SCT recipients during 1994-1998 a median of 160 days after transplantation. The mean interval between first symptoms and diagnosis was 29 days and was still longer for patients with atypical MBI or recipients of corticosteroid therapy. The prevalence of MBI was highest among those who received matched unrelated or mismatched STCs from related donors. Of 31 patients, 20 had tuberculosis, 8 had atypical MBI, and 3 had diagnoses based on histological findings only. Five patients (16%) died, all of whom had received an allogeneic SCT. Because of the increased numbers of unmatched donors and transplantation programs in countries with a high prevalence of tuberculosis, constant vigilance is required to early detect MBI in SCT recipients.

We studied 128 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). Disease at the time of treatment with Imatinib was in chronic phase (CP) in 51 patients, accelerated phase (AP) in 31 and blastic crisis (BC) in 46. Of the 51 patients in CP, 14 were in cytogenetic and two in molecular relapses. The median interval between relapse and Imatinib therapy was 5 months (0–65). A total of 50 patients had failed treatment with donor lymphocyte infusions prior to Imatinib. The overall hemato-logical response rate was 84% (98% for patients relapsing in CP). The complete cytogenetic response (CCR) was 58% for patients in CP, 48% for AP and 22% for patients in BC. Complete molecular responses were obtained in 25 patients (26%), of whom 21 were in CP or AP. With a median follow-up of 9 months, the estimated 2-year survival for CP, AP and BC patients was 100, 86 and 12%, respectively. Out of 79 evaluable patients, 45 (57%) achieved full donor and 11 (14%) mixed chimerism after Imatinib. We conclude that Imatinib has significant activity against CML in relapse after allogeneic SCT. Durable cytogenetic and molecular remissions are obtainable in patients in CP.

Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) have excellent responses with kinase or BCL2 inhibitors, but patients with high risk cytogenetics (del(17p) and/or del(11q)) do not seem to achieve long-term disease control. Allogeneic hematopoietic stem cell transplantation (alloHCT) can result in sustained progression-free survival. As non-relapse mortality (NRM) after alloHCT is partly age-dependent, alloHCT is preferably considered in younger high cytogenetic risk CLL patients, but data of early NRM and longer-term PFS lack for this age group. We focused in this study on younger allo-transplanted CLL patients ( Figure. Figure. Disclosures Dreger: Novartis: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy. Gramatzki:Janssen: Other: Travel/Accommodation/Expenses, Research Funding. Delgado:Janssen: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Schoenland:Jansen: Honoraria, Other: financial support of conference participation, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schetelig:Sanofi: Honoraria.

Background: Over the last decade, there has been a significant increase in the number of patients with Myelofibrosis (MF) undergoing allogeneic stem cell transplantation (SCT). However, scarce information exists on the outcome and management of those patients who relapse following SCT. Moreover, the management of relapse occurring post-SCT is often heterogeneous and ranges from palliation to intensive salvage approaches. We therefore conducted a retrospective EBMT registry analysis of adult MF patients who relapsed following first SCT episode. Results: A total of 1216 adult patients (997 (82%) with Primary MF (PMF) and 219 (18%) with secondary MF (sMF)) underwent 1st allogeneic SCT between 2000 and 2010. A total of 251 patients from this cohort (206 with PMF and 45 with sMF) had conformed relapse ≥ day 30 after HSCT and were included in the analysis. Within this relapse cohort, there were 163 males and 88 females; median age was 55 years old (range 21.5-70 years). A total of 84 patients (33%) had received Myeloablative Conditioning (MAC) and 167 patients (67%) Reduced Intensity Conditioning (RIC). Regarding donor type, there were 123 matched siblings (49%) and 128 unrelated donors (51%). Acute GVHD (aGVHD) status was available for 243/251 (97%) patients; no aGVHD was evident in 143 patients, Grade I-II aGVHD 76 patients, Grade III-IV aGVHD 22 patients and 2 patients with aGVHD ungraded. The median time to relapse after SCT was 7.1 months (range 1-111 months). The median Overall Survival (OS) from the time of relapse was 17.7 months (95% Confidence Intervals 11-24). Collectively, there was a significant difference in survival outcome for those relapsing > 7.1 months post-SCT (median survival 30.3 months post relapse) compared to those relapsing within 7.1 months following the initial SCT episode (median survival 7.9 months post relapse; p Conclusions : This analysis represents the first study to define the outcome of MF patients who undergo relapse following allogeneic SCT. Treatment of relapse presents huge challenges and the heterogeneous management strategies highlighted above reflects current practice where approaches range from palliation through to intensive chemotherapy and 2nd SCT. It is clear from this analysis that early relapse has a much worse prognosis than those who relapse later than 7.1 months post-SCT. There is a definite survival advantage for those who undergo DLI and/or a 2nd SCT procedure, although we acknowledge that those patients undergoing a 2nd SCT represent a highly selected group who are fit enough to undergo such intervention. Moreover, how relapse management practice will change in the era of novel therapies such as JAK inhibitors to bridge towards 2nd SCT is currently unclear and requires evaluation in prospective studies. Disclosures McLornan: Novartis: Research Funding, Speakers Bureau. Finke:Riemser: Research Funding, Speakers Bureau; Neovii, Novartis: Consultancy, Research Funding, Speakers Bureau; Medac: Research Funding. Craddock:Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Speakers Bureau; Sunesis: Honoraria; Johnson and Johnson: Consultancy. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

International audience; The goal of this study was to analyze results and to determine factors affecting outcome of HLA-matched hematopoetic stem cells transplantation (MRD-HSCT) for patients with acute leukemia transplanted in first complete remission in Eastern European countries. Six hundred forty HSCT were performed between 1990 and 2006 for adults with acute myeloid ( = 459) and lymphoblastic ( = 181) leukemia. Two-year leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse incidence were 58 ± 2%, 19 ± 2%, and 23 ± 2%, respectively. The cumulative incidence of NRM decreased from 22 ± 2% for patients treated between 1990 and 2002 to 15 ± 3% for transplantations performed between 2003 and 2006 ( = 0.02), despite increasing recipient age. In a multivariate analysis, time of HSCT affected both NRM and LFS. Among other prognostic factors, the use of TBI decreased relapse incidence and increased the LFS rate. We conclude that results of MRD-HSCT for acute leukemia in Eastern Europe improved over time as a consequence of decreased NRM. The use of TBI containing regimens appears advantagous.

Contains fulltext : 79938.pdf (Publisher’s version ) (Closed access) Allogeneic stem cell transplantation (alloSCT) for patients with refractory anaemia may result in a 50% event-free survival, but the high non-relapse mortality (NRM) precludes a general application of this therapeutic modality. This study evaluated the impact of various pre-transplant variables, including disease duration, intensity of the conditioning regimen, type of donor and year of transplantation on outcome. The study population consisted of 374 patients; 244 were transplanted from human leucocyte antigen (HLA)-identical siblings and 130 patients from matched unrelated donors. The median age was 39 years. One hundred and two patients were transplanted after reduced intensity conditioning (RIC). The overall 4-year survival was 52%. The 4-year survival of patients transplanted with HLA-identical sibling donors and matched unrelated donors was 52% and 50%, respectively. Multivariate analysis showed an improved survival (P = 0.05) and a lower NRM (P = 0.02) when the transplantation was performed in recent years. Increasing age, and disease duration of >12 months were associated with inferior survival. RIC resulted in a similar survival despite an increased relapse risk (P = 0.02). This improved outcome permits alloSCT in patients older than 50 years of age, even with the use of matched unrelated donors. AlloSCT should be preferentially performed early after diagnosis after careful analysis of prognostic variables.

The role of human platelet alloantigens (HPA) in clinical bone marrow allotransplantation was investigated. The leading hypothesis was that HPA alloepitopes act as minor histocompatibility antigens and aggravate graft-versus-host disease (GVHD). To exclude the effect of MHC disparity, only HLA identical donor-recipient pairs were entered into the study. The influence of HPA compatibility on overall survival, occurrence of relapses and haematopoietic recovery was also investigated. A total of 223 patients who received a graft from an HLA-identical sibling, genotyped for HPA -1, -2, -3, -4 and -5, were observed over a post-transplant period of 24 months following the protocol recommended by EBMT. The data from patients having received grafts from HPA compatible donors were compared to data from patients having received grafts that were mismatched in HPA allotypes in the GVH direction. Analysis of the incidence of acute and chronic (GVHD), overall survival, relapse incidence, haematopoietic recovery and some other clinical parameters did not reveal any significant difference between the HPA-matched and -mismatched groups of patients, regardless of their age. Our results give no evidence that HPA-1, -2, -3 and -5 alloantigens should be considered minor transplantation antigens in clinical bone marrow transplantation.

Aim Graft-versus-host disease (GVHD) is dominant complication of the allogeneic hematopoietic stem cell transplantation (aHSCT) which results in significant morbidity and mortality of the patients. GVHD is caused by alloimmune reaction of donor T-lymphocytes against the recipient antigens. The aim of this pilot study was to investigate expression of the genes for 1) activating molecules of Th1 (TBX21) and Th2 (GATA3) lymphocytes and for 2) molecules that affect lymphocyte homing in target tissues during the GVHD development (ITGA4 and ITGB7). Methods Peripheral blood samples were collected to RNA protective medium from 30 patients designated for aHSCT at 7 events, i.e. before conditioning, before aHSCT (day 0), 14, 21, 28, 100 and 180 days after aHSCT. The relative expression of four investigated genes was determined by quantitative real-time PCR using PGK1 as a housekeeping gene. Results Relative expression of all studied genes was decreased after conditioning, which was in accordance with inhibition of the immune system during the preparative regimen. The expression of TBX21 mRNA increased after the transplantation and at 100 and 180 days after transplantation was up-regulated compared to that before conditioning (d100: p 0.005; d180: p Conclusions In summary, mRNA expression of the activating molecule of Th1 lymphocytes (TBX21, T-bet) is up regulated in a longer period after the transplantation. After enlargement of our study group we will further evaluate the mRNA expression of an expanded gene spectrum in relationship with the occurrence and severity of GVHD. Acknowledgment for grant support: IGAMZCRNT12454

Decreased risk of acute gastrointestinal toxicity when substituting methotrexate with mycophenolate mofetil in the prevention of graft-versus-host disease in stem cell transplantation following myeloablative conditioning regimens

Abstract 4485 Purpose Thanks to the development of knowledge in the field of molecular biology, the great progress has been done in risk stratification of patients with acute myeloid leukemia (AML) at diagnosis, in recent years. Based on the recommendations of international expert groups there were identified the patients who may benefit from the allogeneic stem cell transplantation (allo-SCT) as a consolidation of first complete remission (CR). In the absence of an universal marker for minimal residual disease (MRD) measurements, there is still little information about the importance of MRD prior to allo-SCT. Our department has a very good experience with quantitative monitoring of WT1 gene expression as a marker of MRD during treatment of AML. The aim was to retrospectively evaluate the significance of MRD in patients indicated for allo-SCT in 1.CR. Patients and methods Overall 35 patients (pts) in the first morphological CR were transplanted from April 2005 - July 2011. Median age was 46 years (range; 20–63), mens 14, women 21, three good risk, intermediate risk 23, high risk 7 (NA 3). A total of 19 pts achieved CR after second induction (salvage), 11 pts were in 1st iCR. Induction 3+7 was given to 31 pts (4x other), as consolidation has been used HIDAC in 28 pts (7x other). As the graft, peripheral blood stem cells were used in 27 pts, bone marrow in 8 pts. The donor was identical sibling in 15 pts (1x mismatched sibling), matched unrelated donor (MUD) in 10 pts and mismatched UD in 9 pts. Conditioning regimen was myeloablative in 29 pts, reduced-intensity in 6 pts. Median follow-up was 18 months (range; 2–56). The expression of WT1 gene was measured by real-time polymerase chain reaction in peripheral blood according to the European Leukemia Net recommendations. The WT1 expression was related to the expression of a reference gene and the results were calculated with a number of WT1 copies related to 104 copies of ABL gene. The upper limit of normal WT1 expression was set as 50 copies of WT1 to 104 copies of ABL. Before allo-SCT, 25 pts were WT1-negative, ten pts were WT1-positive. Results When comparing the two groups according the MRD status, there was not significant difference in terms of age, risk groups, first induction failure, number of iCR, induction or consolidation type. Also, type of graft, conditioning regimen, or HSCT-CI was not significantly different. The group of WT1-positive pts had more unrelated donors, more aGVHD and shorter follow-up. In terms of cGVHD, the groups were comparable. When comparing the overall survival (OS) and cumulative relapse incidence (RI) of the entire group in terms of: risk group, first induction failure, iCR, consolidations number and incidence of aGVHD, we found no significant difference. Pts with cGVHD had a better OS, lower RI with comparable non-relapse mortality (NRM). In contrast, the MRD status measured by WT1 gene expression appears as clearly significant factor. The outcome of WT1-positive pts is significantly worse in terms of OS (55% vs 83% at 3 years, p = 0.03), RI (50% vs 11% at 3 years, p = 0.008), and there is a trend toward higher NRM (23% vs 5% in 3 years, p = 0.08). Conclusion Our results show that MRD status measured by WT1 gene expression in patients with AML in 1.CR significantly affects their future prognosis. Opportunities to influence the unfavorable prognosis of MRD-positive patients may be more intensive pre-transplantation therapy or earlier immunomodulatory intervention after allo-SCT (pre-emptive DLI). The larger prospective studies are necessary to confirm this hypothesis. The study was supported by scientific project MZ 00023736 granted by the Ministry of Health, Czech Republic. Disclosures: No relevant conflicts of interest to declare.

Abstract 3014 FN2 Background: Allogeneic hematopoietic stem cell transplantation (SCT) is associated with iron overload and iron toxicity, especially in patients with myelodysplastic syndromes (MDS). Causes of this increased iron load are transfusions, ineffective erythropoiesis and, myelosuppressive therapy. Investigators found that iron toxicity (often using serum ferritin as a surrogate marker of iron burden) was associated with an adverse effect on non-relapse mortality (NRM) and overall survival (OS). As pre-transplant anti-leukemic treatment may lead to organ damage which may influence outcome after SCT, our study aimed to minimize the role of previous treatment toxicity by only including MDS patients who had not received intensive anti-leukemic treatment prior to SCT conditioning, allowing more insight in the role of iron toxicity in allogeneic SCT. A retrospective analysis of data from the EBMT registry was carried out after an additional survey within selected EBMT centers. Objectives: This report describes the effect of iron toxicity on OS, NRM and relapse during treatment with myeloablative (MAC) allogeneic SCT in previously untreated adults with MDS. Results: The Chronic Leukemia Working Party of the EBMT collected data of 201 adult patients with cytological proven MDS, according to the WHO classification, who received allogeneic SCT after myeloablative conditioning in 2000–2005. Data were available from 201 patients transplanted in 34 centers. All clinical variables were measured at time of transplantation. Fifty-nine percent of the patients were male (n=119). The median patient age was 49 years (range 18–70). Median time between diagnosis and transplantation was 8 months (range 0, 3–274). WHO classification at transplantation was RA/RARS/5q- 36% (n=72), RCMD 7% (n=15), RAEB-1 17% (n=34), RAEB-2 20% (n=39) and sAML 20% (n=41). A composite iron parameter based on the serum iron levels, transferrin saturation and serum ferritin levels prior to the SCT was used to define a high risk group with serum ferritin >1, 500 ng/ml, and/or transferrin saturation >80% and/or serum >200 mg/l (low/intermediate/high 30% / very high 12% / missing 58%). Variables analyzed were WHO classification groups, iron load, amount of red blood cell (RBC) transfusions prior to SCT (≤20 RBC units 43% / >20 RBC units 20% / missing 37%), age (≤50 years 58% / >50 years 42%), cytogenetics (normal 31% / abnormal 46% / 23% not performed or missing), donor type (HLA id.Sibling 55% / Unrelated44%), match sex recipient-donor (male-female 23% /other 77%), time between diagnosis and transplantation (≤6 months 40% / >6 months 60%), co morbidity (no 45% / yes 26%, missing 29%). Univariate analysis for OS showed a significant impact of WHO-classification (p=0.04), iron load (p=0.055) and, amount of RBC transfusions (p=0.02) but were not significant for age (p=0.23), cytogenetics (p=0.39), donor type (p=0.75), match sex recipient-donor (p=0.82), time between diagnosis and transplantation (p=0.30), and comorbidity scores (p=0, 11). The high risk iron load group show decreased 2-year OS (29% versus 59% in the low risk group) due to a combined higher relapse risk and NRM. Table 1 . shows the most relevant Hazard Ratios and p-values for Cox models for OS, NRM and relapse. For each outcome we created 4 models, each including WHO classification, age, donor type, sex match, time between diagnosis and transplantation, and then adding cytogenetics, and additionally iron load, RBC-transfusions, and comorbidity score, respectively. The first model showed a significant impact of WHO classification at SCT on survival (p=0.028), and relapse (p=0.016). OS NRM Relapse Iron load * 1.59 (.18) 1.48 (.31) 1.93 (.37) RBC transfusion ** 2.07 (.04) 1.95 (.02) 2.58 (.05) Comorbidity score *** 1.46 (.14) 1.69 (.08) 1.14 (.79) * very high versus all others; ** *** yes versus no. Conclusion: These data show that disease stage has a significant impact on outcome. In addition a high number of RBC transfusions has a negative influence on OS, NRM and relapse. Iron load, when adjusted for transfusion numbers does not influence outcome. In our study with relatively low co-morbidity due to short interval between diagnosis and SCT (median 8 months) and the exclusion of patients who received anti-leukemic therapy prior to SCT the influence of co-morbidity on outcome was not significant. Disclosures: No relevant conflicts of interest to declare.

Abstract 4357 Background This retrospective study evaluates outcomes of patients (pts) treated with autologous stem cell transplantation (ASCT) and subsequent therapy for relapsed/refractory Hodgkin lymphoma (HL) who underwent ASCT in 7 transplant centres in Czech Republic. Patients and methods 194 pts with relapsed/refractory HL treated with ASCT (184 single, 10 tandem) between 01/2000 and 06/2009 were analyzed. Overall survival (OS) and progression-free survival (PFS) since the time of ASCT were evaluated according to Kaplan-Meier methods. Outcome of pts relapsing after ASCT was evaluated since the time of relapse. Different salvage modalities after ASCT and their impact on survival were compared with log-rank test. Results Median age of pts at time of ASCT was 33 (range 18-66) years. Best response observed after ASCT: complete remission (CR) in 124 pts (64%), partial remission (PR) in 35 pts (18%), stable disease (SD) in 2 pts (1%) and relapse/ progression in 33 pts (17%). Median follow-up was 44 months (m)(range, 3-108). Projected 5-year OS was 71% (median not reached) and PFS 54% (median 86m). Overall 70 pts progressed/relapsed after ASCT and allogeneic stem cell transplantation (alloSCT) was planned in 38 of them, but carried out only in 25 pts (3 myeloablative and 22 reduced intensity regimens). 37 pts were scheduled for other salvage therapy, 4 pts underwent second ASCT and 4 pts did not receive further treatment. Median survival of 70 pts since relapse after ASCT was 16.9 months. Median survival since relapse after ASCT in pts with or without alloSCT was 31.8 and 12.4 months respectively, but the difference was not statistically significant. Overall 51/194 (26.3%) pts died. 11 of 124 pts died in continuous remission after ASCT due to non-relapse mortality including transplant related mortality in 8pts (6.4%). 40/70 relapsed/refractory pts died: 29 in relapse/progression (20 after salvage treatment, 9 after alloSCT) and 11 pts due to non-relapse mortality (5 after salvage treatment and 6 after alloSCT). Conclusion Efficacy of ASCT was confirmed in 113/194 surviving pts (58%) in continuous remission. Median survival of relapsed pts following ASCT was 16.9 m. AlloSCT seems to improve survival in relapsed/refractory patients, although the difference is not statistically significant. New drugs should be offered to patients failing transplantation treatment. Disclosures: Trneny: GSK: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fresenius: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: New chemotherapeutics protocols, included high dose therapy with hematopoietic stem cell transplantation (HSCT) and anti-CD20 therapy may be curative for many patients with non-Hodgkin’s lymphoma (NHL). However in some cases, standard approach, including autologous HSCT fails. Allogeneic HSCT (allo-SCT) may be effective, however is still associated with high treatment-related mortality (TRM). We report here a retrospective analysis of allogeneic SCT in pts with NHL reported to the Czech National Registry of SCT from four centers in years 1999–2005. Methods: We analysed 57 patients with NHL (41 males, 16 females). Histological subtypes were: diffuse large cell lymphoma (DLBCL), n=16, follicular lymphoma (FL), n= 17, mantle cell lymphoma (MCL), n=8, peripheral T-cell lymphoma, n=7, Burkitt’s lymphoma, n=2 and 7 other unspecified lymphomas. Median age was 50 (19–64) years. Donors were identical siblings in 40 pts (70%) or unrelated volunteers in 17 (30%). Six (11%) pts received bone marrow and 51 (89%) received PBPC. Forty-three (75%) pts received reduce-intensity conditioning (RIC), fourteen (25%) were treated with conventional myeloablative regimen. Twenty-five (44%) patients had previous autologous HSCT. At time of allo-HSCT, thirty-eight (67%) pts had chemosensitive disease, thirteen (23%) were considered as chemoresistant (six were untested). Interval from diagnosis to SCT ranged from 9,5 to 198 months with median 21 months. Results: All pts but one engrafted. Acute graft-versus-host disease (aGVHD) occurred in 18 (31%) pts (11× grade I–II, 7× grade III–IV). Of the 35 evaluable patients sixteen (46%) developed chronic GVHD (12× limited, 4× extensive). The 100-day, 1-year and 3-years TRM rates were 30%, 39% and 42% respectively. Relapse or progression was observed in 26%. With a median folow-up of 31 months (range, 4–108) of living patients, the actuarial overall survival (OS) rates at 3 years were 36%, progression free survival (PFS) 36% and relaps risk 41 %. The 3-years OS rates of patients with DLCL, FCL and MCL were 15%, 53% and 31% respectively. Patients after prior ASCT had significantly less outcome (3-year OS 16% vs 51%, p=0,04). There was not found the correlation between GVHD and relapse rate, the outcome of pts treated with myeloablative regimen and RIC was not significantly different (3-year OS 46% vs 36%, relaps risk 20% vs 47%, p=0,4). There was no diference in OS between related and unrelated transplants (3-year OS 40% vs 35%, p=0,16). We didn’t observe significant diference between pts transplanted in chemosensitive or chemoresistant disease (3-year OS resp PFS 43% vs 23%, p=0,09, resp 39% vs 31%, p=0,14) At time of last follow-up 32 patients were dead and 25 were alive (22 in complete remission). Conclusion: Allogeneic HSCT represents an effective therapeutic option for patients with poor prognosis NHL, however TRM remains the problem as well as high relapse risk in some cases. RIC may be an option for erderly patients but it’s not clear if it offers the same effectivity as standard myeloablative regimen. Transplants from unrelated donors may be probably considered comparable to related.

The influence of different clinical and laboratory parameters and various therapeutic approaches on the survival was retrospectively studied in a group of 142 adult patients with advanced forms of primary MDS: RAEB with > 10% blasts or RAEB-T. Univariate statistical analysis was performed using Kaplan-Meier curves and log-rank2 test. Independent variables for determining survival were studied using proportional hazards regression multivariate analysis. Median survival, estimated 1 year (ES1y) and 3 year (ES3y) survival of patients stratified according to different treatment modalities are shown in the table. Median survival and estimated 1 and 3 year survival of patients stratified according to different treatment approaches. treatment Nr.of patients median survival (months) ES1y (%) ES3y (%) allo SCT (+/− chemotherapy) 31 37,5 90,3 58,0 chemotherapy + auto SCT 6 21,5 100 33,3 combination chemotherapy 47 8,0 40,4 4,3 low-dose chemotherapy 18 5,5 22,2 11,1 demethylating agents 3 11,5 33,3 NE oral single agent chemoth. 6 2,8 0 0 supportive care only 31 3,0 3,2 0 Allogeneic stem cell transplantation (SCT) regardless to the number of bone marrow blasts at the time of conditioning or to whether the patients received combination chemotherapy prior SCT or not was the most significant parameter affecting survival in univariate analysis (χ2=46,3, P 5% bone marrow blasts prior SCT). Our data support the usefulness of combination chemotherapy followed by SCT as an optimal treatment regimen for younger patient with advanced MDS. In future studies, combination chemotherapy followed by treatment with demethylating agents might be a promising approach to prolong survival in patients with advanced MDS who are not indicated for SCT.