HLA-compatible Unrelated Donor Research Articles

Clonal Hematopoiesis Is Common in Unrelated Stem Cell Donors but Has No Impact on Patient Outcome after Hematopoietic Stem Cell Transplantation

Introduction. Clonal hematopoiesis (CH) has been associated with increased mortality mainly due to associations with cardiovascular diseases and hematologic cancer. Previous studies with predominantly related stem cell donors suggest that donor CH modulates graft-versus-host reactions and may augment graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (alloHCT). The impact of donor CH in the setting of unrelated alloHCT remains to be determined. To address this question, we initiated a joint study of the Transplant Complications Working Party of EBMT and DKMS. Patients and Methods. Donor samples from the time of stem cell donation were taken from the Collaborative Biobank. Patient baseline and outcome data were retrieved from the EBMT registry. Unrelated donor-recipient pairs were selected for a minimum donor age of 35 years. CH analysis was performed with an error-corrected ultra-deep NGS assay for 45 genes with a median sensitivity of 0.2% variant allele frequency (VAF). Accuracy of low frequency CH findings was checked by cross validation with an orthogonal assay. The primary objective was to assess the impact of donor CH on overall survival (OS). Major secondary endpoints were the risk of relapse/progression and non-relapse mortality (NRM), cumulative incidences of acute and chronic GVHD and event-free survival (EFS). All endpoints were evaluated with (cause-specific) multivariable Cox regression models. Adjustment factors were patient and donor age, diagnosis, disease risk index, Karnofsky performance status, conditioning intensity, GVHD-prophylaxis, graft source, HLA-match, sex match and CMV match. We did not adjust for multiple testing. Results. Data from 2584 unrelated donor-recipient pairs were analyzed. Median patient follow-up after alloHCT was 60 months. The median donor age was 46 years (range, 39-61 years). The median patient age was 54 years (range, 0-79 years). Indications for alloHCT were AML (44%), ALL (10%), MDS (10%), MPN (6%), B-cell lymphoma (6%), Multiple Myeloma (5%), CML 3%, inherited disorders (3%), CLL 2% and other (13%). Transplantations were performed between 2005 and 2018. In vivo or ex vivo T-cell depletion (TCD) was used in 81% of transplants, PTCY in 5% and no TCD in 14%. Mutations in DNMT3A, TET2, and ASXL1 defined CH most frequently. The distribution of donor CH across leukemia driver genes was comparable to previous reports (Panel A). With 0.2% (2%) VAF cutoffs, rates of DNMT3A-mutations were 19% (2%) among donors younger than 41 years compared to 37% (6%) among donors aged 55 years and higher. Corresponding rates for 0.2% (2%) VAF cutoffs for total CH were 38% (4%) among donors younger than 41 years compared to 67% (14%) among donors aged 55 years and higher. We tested systematically increasing VAF cutoffs (≥0.2% versus <0.2%, ≥1% versus <1%, ≥2% versus <2%, ≥5% versus <5%, and ≥5% versus <0.2%) for DNMT3A-CH and total CH for associations with clinical endpoints. Panel B shows results for multivariable regression analyses for total donor CH. Although we observed trends towards increased mortality and inferior EFS for some cutoffs, no incremental impact of donor CH with higher VAF was found and no systematic changes of the risk for GVHD and relapse/progression were observed. Conclusions. We conclude that donor CH has no significant impact on the risk for GVHD, relapse and survival in the context of HLA-compatible unrelated donor alloHCT with GVHD-prophylaxis based predominantly on T-cell depletion with ATG.

Immediate Allogeneic Hematopietic Stem Cell Transplantation for Patients with NPM1-Mutated AML in Molecular Relapse

BackgroundAccording to ELN 2017 classification NPM1-mutated AML is characterized as favorable or intermediate risk depending on the coexistence of FLT3 mutations. For pts with favorable risk profile allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) is not recommended. Because NPM1 mutations are stable, and persisting or increasing levels are a strong predictor of relapse, regular monitoring of measurable residual disease (MRD) by quantitative PCR (qPCR) is recommended. Early HSCT in molecular relapse can be an effective treatment strategy and avoid possible complications of reinduction chemotherapy. From 2014 we started to search for a donor immediately after molecular relapse and proceed to HSCT without reinduction chemotherapy.MethodsMRD was monitored at least every 3 months (mos) in all pts with NPM1-mutated AML in CR by qPCR in bone marrow or peripheral blood. Molecular relapse was defined as an increase of MRD above a cut-off of 1% NPM1/ABL1. The conditioning regimen consisted of Treosulfan (Treo, 30g/m 2) and Fludarabin (Flu, 120mg/m 2). In pts with hematological relapse or a very high NPM1 ratio at the time of HSCT Melphalan (Mel, 100mg/m 2) was added before Treo/Flu to induce aplasia. Donors were HLA-compatible unrelated donors in 10/13 pts, HLA identical sibling in 1 pt and haploidentical related donors in 2 pts. All pts were transplanted with G-CSF stimulated peripheral blood stem cells. Immunosuppression consisted of ATG and Ciclosporin in combination with MTX or MMF and posttransplant Cyclophosphamide for haploidentical HSCT (2 pts).Results17/37 pts fit for allogeneic transplantation relapsed after initial induction and consolidation therapy. 4 pts showed a hematological relapse. In 13/15 pts (median age 52 (37-72) years) a molecular relapse was detected at a median of 9 (6-42) mos after diagnosis, these pts are analyzed here. 10/13 relapses occurred within 12 mos after CR. 11/13 pts relapsed after achieving MRD negative remission, 2 pts progressed from MRD positive hematological remission. Median time from increase in MRD to HSCT was 2 (2-4) mos. Even after this short time period, 6/13 pts developed a hematological relapse before start of conditioning therapy. Together with 3 pts with a high molekular NPM1 level, these 6 pts received melphalan for induction of aplasia before starting Treo/Flu. Although hematological regeneration took longer for these pts compared to pts without melphalan, there were not more infectious or bleeding complications. All 13 pts reached complete hematological and molecular remission after HSCT. After a median follow-up of 20 (4-47) mos all pts are in CR. 2 pt relapsed 6 and 13 mos after HSCT, but reached CR again after DLI (1 pt.) and venetoclax(1pt). In all pts the duration of second CR after HSCT lasted longer than the first CR.ConclusionThis analysis shows the efficacy and feasibility of early allogeneic HSCT without reinduction chemotherapy in molecular or early hematological relapse for NPM1- mutated AML pts. For this strategy pts have to be monitored strictly at regular intervals after end of chemotherapy consolidation, because most relapses can be detected at molecular level. DisclosuresNo relevant conflicts of interest to declare.

A Phase II Trial Evaluating the Use of the Histone Deacetylase Inhibitor Panobinostat for Graft-Versus-Host Disease (GVHD) Prevention

Introduction: The use of histone deacetylase inhibitors has shown promising results in the prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplant (HCT) (Choi et al, Lancet Oncology, 2014). In this protocol, we will build on prior experience by adding panobinostat to tacrolimus and sirolimus for GVHD prevention (Pidala et al, Haematologica, 2012 and idem, 2015). Panobinostat has been proven to be tolerable in our prior study of GVHD treatment in addition to glucocorticoids (Perez et al, ASH 2014 Abstract), in myelodysplastic syndrome (MDS) maintenance (Bug et al, ASH 2015 Abstract), and in early post-HCT epigenetic therapy (panobinostat and decitibine) followed by donor lymphocyte infusion (Cornelissen et al, ASH 2016 Abstract). We hypothesize that panobinostat added to tacrolimus-sirolimus may abolish GVHD while sparing the graft-versus-leukemia effect by enhancing T regulatory cell development and modulating antigen presentation.Methods: This is a phase II Simon's minimax two-stage design; the null hypothesis will be rejected if the number of patients with grade II-IV aGVHD is 12 or less among 38 evaluable patients (≤31.6% incidence rate at day 100). To date, we have enrolled 27 patients with hematological malignancies (3 with AML, 3 with ALL, 3 with MPN, 6 with MDS, and 1 each with CML, chronic neutropenia, PTCL, and BPCDN) and a median age of 56 years (range, 29-72 years). These patients have been followed for at least 100 days after an HLA-compatible unrelated-donor (n=19) or related-donor (n=6) HCT. The conditioning regimen was BU/FLU AUC 5300 for 4 days (16 patients), BU/FLU AUC 3500 for 4 days (1 patient), or fludarabine/melphalan 140 mg/m2 (10 patients). All participants received G-mobilized peripheral blood stem cells. Panobinostat at 5 mg orally 3 times/week was initiated on day -5 or -6 and continued for 26 weeks; panobinostat stopping criteria included GVHD requiring corticosteroids (1 mg/kg) or toxicity. Tacrolimus was given starting on day -3, with taper recommended from day +50, and sirolimus was started on day -1 with taper recommended from day +365.Results: Engraftment occurred at a median of 14.5 days (range, 12-18 days) for ANC over 500/µL and median of 15.5 days (range, 10-27 days) for platelets over 20,000/µL. Sinusoidal obstruction syndrome was seen in 1 patient (resolved). Among 27 patients, 7 completed panobinostat treatment as planned at day 100. The other 20 patients stopped panobinostat due to GVHD treated with 1 mg/kg corticosteroids (n=4), myelosuppression possible related to panobinostat (n=8), mucositis (n=2), QTCF prolongation (n=1), comorbidities (n=5), patient refusal (n=1), peripheral edema/renal failure possible related to panobinostat (n=1), rash/angioedema (n=1) definitively related to panobinostat), and facial erythema possible related to panobinostat (n=1). Among 27 evaluable patients, aGVHD was seen in 6 of 27 patients (22%), with 5 patients having grade II (4 responded to corticosteroids; 1 resolved with no corticosteroids) and 1 having grade III GVHD (Jakafi stopped pre-HCT resolved with re-initiation). We did not observe an increase in infection risk. None of the 27 patients died within 100 days, and 7 relapsed at 3-8 months (3 with AML FLT3+, 1 with AML DNMT3A and IDH1 mutations, 1 with ALL, 1 with MPN and 1 with MDS-complex cytogenetics).Conclusions: The combination of tacrolimus-sirolimus-panobinostat seems to be an effective strategy to reduce aGVHD in myeloablated unrelated-donor or related-donor transplant with a 22% incidence of aGVHD compared with 43% reported with tacrolimus-sirolimus in our previous study. Follow-up and accrual completion are required, and correlative studies are planned that will compare results with control patients receiving tacrolimus-sirolimus only. DisclosuresKharfan-Dabaja:Alexion Pharmaceuticals: Speakers Bureau; Incyte: Speakers Bureau; Seattle Genetics: Speakers Bureau.

ТРАНСПЛАНТАЦИЯ ПУПОВИННОЙ КРОВИ У ДЕТЕЙ: ОБЗОР ЛИТЕРАТУРЫ И ОПЫТ ОДНОГО ЦЕНТРА

Umbilical cord blood (CB) has been used successfully as hematopoietic stem cells (HSCs) in adults and adults with malignant and non-malignant diseases in which there are indications for HSC transplantation (HSCT), and when an HLA-compatible related or unrelated donor is not available. CB, like any source of HSC, has certain advantages and disadvantages, which also determine the features of its use in transplantation. The article presents the experience of using CB as a source of HSC in pediatric patients at the Russian Children's Clinical Hospital (RCCH). Materials and methods of research: in a retrospective single-center continuous non-randomized uncontrolled open study includes 16 patients with various malignant diseases and 16 patients with non-malignant diseases, who underwent CB transplantation in the bone marrow transplantation department of the Russian Children's Clinical Hospital from 1997 to 2012. The peak of CB transplant activity occurred in the period from 2006 to 2010. The age of the patients at the time of the transplantation ranged from 6 months to 14 years. In 10 patients, a CB transplant from HLA-identical related donors was used, in 22 – from unrelated HLA-identical and HLA-incompatible for 2 or more antigens obtained from domestic CB banks. In addition to CB, six children were given bone marrow or peripheral blood stem cells from HLA-identical siblings as a transplant. The majority of patients (n=20) received one CB sample, 10 patients – 2 samples and two – 3. Results: implantation of the transplant was recorded in 27 children (84%), which 17 (53%) were alive, 10 (31%) died at different timesof post-transplant period. In 5 (16%) patients, implantation did not occur, of which one (3%) died, the cause of mortality in pediatric patients was a relapse of the underlying diseases. Acute graftversus-host reaction (GVHD) after CB transplantation was assessed in 27 (84%) patients of this study, among them 17 (63%) were diagnosed with acute GVHD stages I-II, 3 (11%) – stage III–IV (life-threatening form). Chronic GVHD was assessed in 18 (56%) patients included in the study, with 5 (28%) diagnosed with a limited form and 3 (17%) with an extensive form. Overall survival (OS) for the entire group of patients (n=32) was 58,3±8,8%, 5-year dormant survival rate (DSR) – 53±8.8%. OS in non-malignant diseases was higher (68%) than for malignant diseases (56%), but no statistically significant differences in OS were obtained in the two groups (p>0,05), as well as when comparing OS and DSR when using one or several samples of CB. Conclusion: CB remains available and acceptable source of stem cells for HSCT. At our center, the survival rates of patients after CB transplantation are comparable to those of international registries. The improvement of the method and the results of haploidentical SCT in recent years has led to a decrease in interest and transplantation activity (including in our center) using CB as a source of HSC. However, the unexplored antileukemic potential of CB stem cells, as well as a number of potential resources for improving and optimizing the use of this HSC source, may increase the chances of future CB transplantation.

Prospective KIR genotype evaluation of hematopoietic cell donors is feasible with potential to benefit patients with AML

Donor KIR and recipient HLA combinations that minimize inhibition and favor activation of the NK repertoire are associated with improved outcomes after allogeneic hematopoietic cell transplantation (HCT) in patients with myeloid neoplasia. We prospectively evaluated a weighted donor ranking algorithm designed to prioritize HLA-compatible unrelated donors (URDs) with weak inhibitory KIR3DL1/HLA-Bw4 interaction, followed by donors with nontolerized activating KIR2DS1, and finally those with KIR centromeric B haplotype. During donor evaluation, we performed KIR genotyping and ranked 2079 URDs for 527 subjects with myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Among all patients, 394 (75%) had at least 1 KIR-advantageous donor, and 263 (50%) underwent HCT. In patients with AML, KIR3DL1 weak inhibition provided protection from relapse. Compared with KIR3DL1-Weak Inhibiting donors, KIR3DL1-Noninteracting donors were associated with increased risk of relapse (HR, 2.97; 95% CI, 1.33-6.64; P = .008) and inferior event-free survival (EFS; HR, 2.14; 95% CI, 1.16-3.95; P = .015). KIR3DL1-Strong Inhibiting donors were associated with HR, 1.65 (95% CI, 0.66-4.08; P = .25) for AML relapse and HR, 1.6 (95% CI, 0.81-3.17; P = .1) for EFS when compared with the use of KIR3DL1-weak inhibiting donors. Donor KIR2DS1/HLA-C1 status and centromeric KIR haplotype-B content were not associated with decreased risk of AML relapse. There was no benefit to KIR-based donor selection in patients with MDS. This study demonstrates that donor KIR typing is feasible, and prioritization of donors with certain KIR3DL1 genotypes may confer a protection from relapse after HCT in patients with AML.

Prospective Multicenter Phase 3 Study Comparing 5-Azacytidine (5-Aza) Induction Followed By Allogeneic Stem Cell Transplantation Versus Continuous 5-Aza According to Donor Availability in Elderly MDS Patients (55-70 years) (VidazaAllo Study)

Introduction:5-azacytidine treatment prolongs survival in older patients with high-risk MDS compared to standard of care options outside allogeneic stem cell transplantation (AHSCT) wich is still the only potentially curative treatment option that is however associated with a considerable treatment-related morbidity and mortality (TRM). Reduced-intensity conditioning (RIC) prior to transplantation has broadened the application of this therapeutic approach also to elderly MDS patients.Here we present results from a prospective multicenter trial of the German MDS and Cooperative Transplant Study Group comparing 5-azacytidine (5-Aza) treatment alone with 5-Aza induction followed by AHSCT according to donor availability in elderly patients with newly-diagnosed untreated HR MDS aged 55-70 years (EudraCT Number 2010-018467-42). Primary endpoint was overall survival (OS) at three years after 5 Aza induction in both arms; major secondary endpoints were to assess the response rate, event-free survival (EFS) at three years, toxicity, treatment-related mortality (TRM) and the impact of the comorbidity-index (HCT-CI) on outcome in both treatment arms.Methods and PatientsPatients with proven de novo or therapy-related MDS / CMML (WBC <13 GPT/l) according to FAB and risk profile according to IPSS: intermediate II-risk or high-risk or intermediate I with high-risk cytogenetic and patients with secondary AML (according to WHO) and blasts ≤ 30 % (= RAEB-t according to FAB) and sufficient organ function, could be included.A donor search was started at the time of inclusion and all patients were scheduled to receive 4 to 6 cycles of 5-Aza induction therapy. In case a HLA -identical sibling or a 10/10 HLA compatible unrelated donor could be identified during the first cycles of 5-Aza and patients had at least stable disease they were allocated for a busulfan-based RIC allograft. In case no suitable donor could be identified 5-Aza was continued until progression or unacceptable toxicity. This protocol-defined primary analysis uses the full 5% alpha error for the primary analysis. A final follow-up analysis will be performed once all patients have been followed-up at least for three years but no later than January 2019.ResultsBetween June 2011 and November 2016 190 patients with a median age of 63 years from 14 German centers were included into the trial. Following 5-Aza induction, only 109 out of 190 patients (57%) were eligible for allocation to one of the treatment arms and proceeded to AHSCT (n=83) or continued 5-Aza therapy (n=26). Reasons for premature study termination of 81 patients (43%) within the first 5-Aza cycles included progressive disease (n=25; 31%), death (n=14; 17%), inclusion or exclusion criteria not fulfilled (n=18, 22%), withdrawal of informed consent (n=7; 9%), adverse events (n=7; 9%) or other reasons (n=10; 12%).Regarding the primary study endpoint and after 5 Aza induction therapy in an intention to treat analysis the OS at 3 years was 49% (95% CI: 36-61%) after AHSCT and 22% (95% CI: 6-44%) after continuous treatment with 5-Aza (p= 0.027). The time dependent Hazard ratio for AHSCT decreased over time: while at 1 year the HR was still 1.4 due to early TRM, this HR decreased to 0.35 at 2 years and 0.09 at 3 years. EFS at 3 years was 35% (95% CI: 22-48%) after AHSCT and 0% after 5-Aza continuous treatment (p< 0.001). The TRM after AHSCT at 1 and 3 years was 17% (95% CI 10-26%) and 23% (95% CI: 14-33%), respectively.ConclusionsThis prospective phase 3 study comparing 5-Aza followed by AHSCT with continuous 5-Aza therapy in older patients (55 to 70 years) suffering from higher-risk MDS demonstrates an improved EFS and OS in favor of AHSCT. Induction therapy with 5-Aza prior to AHSCT is associated with a considerable rate of drop outs due to progression, adverse events, and mortality prior to AHSCT.The study was registered under ClinicalTrial.gov: NCT01404741.The study was supported by a research grant from Celgene, Germany. [Display omitted] DisclosuresKroeger:Celgene: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; JAZZ: Honoraria; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Novartis: Honoraria, Research Funding. Bethge:Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Kobbe:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding; Roche: Honoraria, Research Funding. Bug:Novartis Pharma: Honoraria, Research Funding; Jazz Pharmaceuticals: Other: Travel Grant; Celgene: Honoraria; Astellas Pharma: Other: Travel Grant; Janssen: Other: Travel Grant; Amgen: Honoraria; Neovii: Other: Travel Grant. Scheid:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Krönke:Celgene: Honoraria. Stelljes:Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria; MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Beelen:Medac: Consultancy, Other: Travel Support. Platzbecker:Celgene: Research Funding.

Long-Term Survival after Transplantation in Patients with Chronic Myeloid Leukemia from HLA-Compatible Unrelated Donors: May the Stem Cell Source Influence the Outcome?

IntroductionAllogeneic hematopoietic stem cell transplantation (alloSCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes regarding graft sources are not well described.ResultsHere the outcomes of CML after alloSCT with bone marrow (BM, n=134) were compared to those of peripheral blood stem cell (PBSC, n=172) in the HLA-compatible unrelated donor setting. Patients were transplanted in 1st CP (Bone marrow transplantation (BMT), n=100, and Peripheral blood stem cell transplantation (PBSCT), n=103), in >1st CP (BMT, n=24, and PBSCT, n=52) and in blast crises (BMT, n=10, and PBSCT, n=17). Median follow-up were 54 months after BMT and 106 months after PBSCT. No significant differences were found in the incidence of acute and chronic graft-versus-host disease (GvHD) between both study-groups. The 5-year estimated probability of hematological relapse was 11% for patients in 1st CP CML and 49% for patients in advanced disease after BMT (p<0.001) and 18% for patients in 1st CP and 22% for patients in advanced disease after PBSCT (p= n.s.). The estimated probability for 10-year overall survival (OS) for patients in 1st CP and patients in advanced stages of CML were 58% and 20% after BMT and 59% and 52% after PBSCT, respectively (not significant for 1st CP and p<0.0001 for advanced stages). In the multivariate analysis patient age (age > 40 years), disease stage, acute GvHD, chronic GvHD and immunprophylaxis with use of ATG influenced OS significantly. For leukemia-free survival, the following risk factors were significantly in the multivariate analysis, graft source, patient age, gender constellation, disease stage, acute GvHD and chronic GvHD.ConclusionsThis large trial show significant difference between transplant recipients who received PBSC and those who received BM from unrelated donor. These finding may influence the selection of a graft source for alloSCT from unrelated donor. DisclosuresDührsen:Amgen: Research Funding; Gilead: Consultancy, Honoraria; Janssen: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Beelen:Medac: Consultancy, Other: Travel Support.

What compatibility in 2017 for the haematopoietic stem cell transplantation?

The diversification of potential donors to perform stem cell allografts now enables to propose a compatible graft cell source adapted to the different clinical situations. Transplants with a geno-identical sibling donor, otherwise with the most HLA-compatible unrelated donor, remain the first-line solutions. Alternative transplants allow to graft patients having no donors in international registries, owing to the rarity of their HLA typing. They are carried out with fairly incompatible grafts and are therefore limited by the existence in the recipient of preformed anti-HLA antibodies which predispose to their rejection. The simple prevention of acute Graft-versus-host disease in haplo-identical transplants, as well as the availability of donors, explain why they have very often replaced placental stem cell transplants. These latter remain useful for pediatric patients or in the absence of family donors.

Effectiveness of Search for an Unrelated Donor of Hematopoietic Stem Cells using Russian Date Base "Bone Marrow Donor Search": Experience of Raisa Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation

Background &amp; Aims. The key condition for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the presence of HLA-compatible related or unrelated donor. If related donor is not found, further search is carried out in the Bone Marrow Donor Worldwide (BMDW) international data base, which is not effective enough (about 80-85 %), because of genotype specificity of Russian Federation residents. The recruitment procedure using BMDW takes a lot of time and is expensive. Therefore, there are good reasons to develop an alternative Russian data base, Bone Marrow Donor Search (BMDS), which includes data from Russian bone marrow donor registries and has a good potential. The aim is to evaluate the effectiveness of hematopoietic stem cell (HSC) donor search and transplant quality using the BMDS search system. Methods. 34 allo-HSCT recipients with malignancies and hematological diseases were enrolled in the study in RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation from November, 2012, to March, 2016. A HLA-compatible donor was found for each patient in the BMDS (www.bmds.info), which includes data from 13 Russian registries of HSC donors. Results. 34 allo-HSCTs were performed from unrelated donors recruited using Russian registries: 1 in 2012; 3 in 2013; 5 in 2014; 21 in 2015; and 4 in the 1&lt;sup&gt;st&lt;/sup&gt; quarter of 2016. The greatest effectiveness of the BMDS search was in 2015 (14 %, n = 17). In 30 cases (88.2 %) a complete 10/10 compatibility for 5 HLA-gene loci was observed; in 4 cases (11.8 %) there was an incomplete compatibility (9/10). AB0 compatibility was only in 7 cases (20.6 %). In 15 cases (44.1 %) bone marrow was used for transplant harvesting; in 19 cases (55.9 %) peripheral blood stem cells were harvested by means of cytapheresis. The CD34+ count in the transplant was 1.2-12.0 х 10&lt;sup&gt;6&lt;/sup&gt; CD34+ cell/kg (median: 5.0 * 10&lt;sup&gt;6&lt;/sup&gt; CD34+ cell/kg). Engraftment was observed in 79.4 % of cases (п = 27), graft failure in 17.7 % of cases (n = 6), and early posttransplant mortality in 2.9 % of cases (n = 1). Conclusion. There was an increasing efficiency of search for a HLA-compatible unrelated HSC donor using a Russian BMDS search system for Russian residents with a graft quality similar to the one found in the international BMDW database.

Infectious complications following allogeneic stem cell transplantation by using anti‐thymocyte globulin‐based myeloablative conditioning regimens in children with hemoglobinopathies

Anti-thymocyte globulin (ATG) has been used to prevent graft failure/rejection in the setting of allogeneic stem cell transplantation (allo-SCT) for hemoglobinopathies; however, epidemiology data for transplant-related infections in this population are scarce. We retrospectively analyzed the epidemiology of bacterial, fungal, viral, and parasitic infections in a cohort of 105 children and adolescents with β-thalassemia (n=100) or sickle cell disease (n=5) who underwent allo-SCT using human leukocyte antigen (HLA)-identical sibling (n=96) or HLA-compatible unrelated donors (n=9) in a single institution. All patients received an ATG-based conditioning regimen. The cumulative incidence of cytomegalovirus (CMV) viremia was 45.7% (95% confidence interval [CI] 33-55%), developing at a median of 48 (range 12-142) days without evidence of overt CMV disease. Herpes zoster developed in 8 patients at a median of 12months post transplant, while 10 patients presented with late onset hemorrhagic cystitis at a median of 35days post transplant. The cumulative incidence of bacteremia was 17.1% (95% CI 10.6-25%), occurring at a median of 74 (range 24-110) days. No patient developed probable or definite invasive fungal infection. Four deaths were recorded; 2 of them were attributed to infections (toxoplasmosis and Pneumocystis jirovecii pneumonia, respectively). The rate of infections after allo-SCT, using an ATG-containing preparative regimen, in our population of pediatric patients with hemoglobinopathies is comparable to that reported elsewhere with the use of non-ATG containing regimens.

Genes of killer cell immunoglobulin-like receptors and their HLA ligands after allogeneic hematopoietic stem cell transplantation in myeloid leukemia patients

To study the impact of the genes of donor killer cell immunoglobulin-like receptors (KIR) and HLA-KIR ligands on overall (OS) and event-free survival (EFS) rates in patients with myeloid leukemia after transplantation with allogeneic hematopoietic stem cells (allo-HSCT) from HLA-identical related and HLA-compatible unrelated donors. The investigation enrolled 29 patients who had undergone allo-HSCT from KIR-genotyped donors at the Department of Bone Marrow Transplantation, Hematology Research Center (see symbol) in 2010-2013. OS and EFS rates after allo-HSCT were calculated using the Kaplan-Meier method. The main predictor of recurrence and survival in patients after allo-HSCT was a recurrence-risk group the patient belonged to before transplantation. The standard-risk group patients whose donors had telomeric gene-content motifs of KIR-B haplotypes had higher EFS rates than those whose donors lacked these genes. The standard-risk patients homozygous for HLA-1 alleles (i.e. without HLA-C2 ligand) tended to have higher EFS rates, so did the patients without HLA-Bw4 ligand. The donors having telomeric gene-content motifs of KIR-B haplotypes are more preferred for allo-HSCT for patients with myeloid leukemia as the presence of donor telomeric KIR-B genes increases EFS rates in standard-risk patients.

– Updated Results from the Bridge Trial: Long-Term Survival and Impact of Donor Availability – Clofarabine Salvage Therapy Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory AML

Background: In relapsed or refractory acute myeloid leukemia (AML), long-term disease-free survival may only be achieved with allogeneic hematopoietic stem cell transplantation (HSCT). Within the BRIDGE Trial, the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT was studied. Here, we report long-term survival data and the impact of donor availability at the time of study enrollment. The BRIDGE trial (NCT 01295307) was a phase II, multicenter, intent-to-transplant study.Patients and Methods: Between March 2011 and May 2013, 84 patients with relapsed or refractory AML older than 40 years were enrolled. Patients were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2, days 1-5). Patients with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2, day -6 to -3, and melphalan 140 mg/m2 on day -2. In patients with partially matched unrelated donors, ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil.Results: Forty-four patients suffered from relapsed AML and 40 patients had refractory disease. The median patient age was 61 years (range 40 – 75). According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as intermediate I, 17% as intermediate II and 20% as adverse risk.The overall response rate assessed at day 15 after start of CLARA was 80% (defined as at least a marked reduction in BM blasts or BM cellularity and absence of blasts in the peripheral blood) with 31% of patients having less than 5% BM blasts at that time. Seventeen patients did not respond to CLARA, and were subsequently treated off-study. Due to early death, three patients were not evaluable for treatment response. Overall, 66% of the patients received HSCT within the trial. Donors were HLA-identical siblings in eight cases (14%), HLA-compatible unrelated donors in 30 cases (55%) and unrelated donors with one mismatch in 17 cases (31%). Treatment success was defined as complete remission (CR), CR with incomplete recovery (CRi) or CRchim (BM donor chimerism >95% and absolute neutrophil count >0.5/nL) on day 35 after HSCT. Treatment success was achieved in 61% of the patients. With a median follow up of 25 months, the OS for all enrolled patients at two years was 42% (95% CI, 32% to 54%). (Figure 1) The Leukemia-free survival at two years for those 51 patients who achieved the primary endpoint was 52% (95% CI, 40% to 69%). (Figure 2)At the time of enrollment, 14% of patients had a related donor and 33% had an unrelated donor available. In 46% of the patients, donor search was initiated at the time of enrollment. For 7% of patients, donor search was unsuccessful prior to enrollment and reinitiated. The OS at 2 years for patients with a related or an unrelated donor available was 75% (95% CI, 54% to 100%) and 47% (95% CI, 31% to 71%), respectively, while it was 29% (95% CI, 18% to 48%) for patients for whom donor search was initiated at time of enrollment (p = .09).Conclusions:Salvage therapy with CLARA, and subsequent conditioning with clofarabine and melphalan prior to allogeneic HSCT, provides good anti-leukemic activity in patients with relapsed or refractory AML. Fast unrelated donor search and work up, with conditioning in aplasia allowed a high rate of successful HSCTs. The leukemia-free survival for this group of elderly, high risk AML patients is very promising. [Display omitted] [Display omitted] DisclosuresMiddeke:Genzyme: Speakers Bureau. Off Label Use: Clofarabine for AML. Schetelig:Genzyme: Research Funding; DKMS German Bone Marrow Donor Center: Employment.

Allogeneic HCT in Patients with 17p-CLL: Results of a Non-Interventional Study of the EBMT & Eric

Introduction17p-/TP53-mutated CLL (17p- CLL) represents approximately 5 to 10% of newly diagnosed CLL cases. Patients with this abnormality have a poor prognosis after chemo-immunotherapy. According to current guidelines, allogeneic hematopoietic cell transplantation (HCT) is recommended in 17p- CLL cases as part of the first- or second-line treatment. In 2010, the European Society for Blood and Marrow Transplantation (EBMT) and the European Research Initiative on CLL (ERIC) started a non-interventional study, to evaluate the outcome of allogeneic HCT in 17p-CLL. Here we report first results from this study.Patients & MethodsMajor eligibility criteria were 17p- CLL in complete or partial remission after first-line therapy or treatment of relapse, age below 70 years, availability of an HLA-compatible related or unrelated donor with up to one HLA-mismatch at HLA-A, -B, -C or DRB1. The primary objective was to determine relapse-free survival.ResultsForty-one patients (30 males, 11 females) from eleven transplant centres were registered for this study between June 2010 and September 2012. The median age was 59 years (range, 28 to 70 years). Twelve patients (29%) were transplanted in first remission. The median number of pre-treatments was 2 (range, 1 to 7) and included alemtuzumab in 31 patients (76%). The remission status at HCT was reported as partial remission in 31 patients (76%) and as complete remission in 10 patients (24%). The median time between diagnosis and HCT was 35 months (range, 4 to 229 months) and the median time between first treatment of CLL and HCT was 12 months (range, 2 to 227 months). Myeloablative conditioning was administered in 3 patients (7%), fludarabine-based reduced-intensity conditioning in 25 patients (61%) and non-myeloablative conditioning, based on 2 Gray TBI, in 13 patients (32%). Donors were HLA-identical siblings for 11 patients (27%), well-matched HLA-compatible unrelated donors for 25 patients (61%) and partially matched unrelated donors for 5 patients (12%). Thirteen patients received ATG. Fifteen patients experienced grade II to IV graft-versus host disease. By July 2014, 27 patients were alive and 14 patients had died. From the deceased patients, 4 patients died subsequent to relapse and 10 patients died without relapse. Causes of death were GVHD in 7 patients, infection in one patient and other causes in 2 patients. The median observation time for living patients was 16 months (range, 3 to 36 months). The probability of relapse-free survival (see also Figure 1) and overall survival at 2 years was 56% (95% CI, 42% to 74%) and 67% (95% CI, 51% to 83%). At two years the cumulative incidences of relapse and non-relapse mortality were 20% (95% CI, 6% to 34%) and 24% (95% CI, 10% to 39%).ConclusionsWhen considering the high disease-specific risk and the median age of 59 years at transplantation of this cohort of patients, we present favourable early results after allogeneic HCT for patients with 17p- CLL. Non-relapse mortality, mainly caused by GVHD, compromised relapse-free survival. The data suggests that allogeneic HCT remains an attractive treatment option, especially for patients with a low transplant risk and a high disease-specific risk of mortality. These results may serve as benchmark for new drugs which are currently under clinical development or have recently received approval for this indication. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Successful treatment of myelodysplastic syndrome and Behcet colitis after allogeneic hematopoietic stem cell transplantation

Successful treatment of myelodysplastic syndrome and Behcet colitis after allogeneic hematopoietic stem cell transplantation

Clofarabine Salvage Therapy Prior To Allogeneic Hematopoietic Stem Cell Transplantation In Patients With Relapsed Or Refractory AML – Results Of The Bridge Trial –

BackgroundIn relapsed or refractory acute myeloid leukemia (AML) long-term disease-free survival may only be achieved with allogeneic stem cell transplantation (HSCT). However, only about 40% of patients (pts) with relapsed AML receive HSCT. A number of factors contribute to this low rate, among them, a moderate activity of currently available salvage regimens and accumulating toxicity of chemotherapy. Clofarabine is considered to have a favorable risk-benefit ratio in this indication and has been successfully used in conditioning regimens. Our goal was to study the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT. Here, we report the results of the BRIDGE trial (NCT 01295307), a phase II, multicenter, intent-to-transplant study. Patients and MethodsBetween March 2011 and May 2013, 84 pts with relapsed or refractory AML older than 40 years were enrolled. Pts were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2 days 1-5). Pts with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2 day -6 to -3 and melphalan 140 mg/m2 on day -2. In pts with partially matched unrelated donors ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil. ResultsMedian age was 61 years (range 40 – 75). Forty-four pts suffered from relapsed AML and 40 pts had refractory disease. According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as interm. I, 17% as interm. II and 20% as adverse risk. Complex and monosomal karyotypes were present in only 12% and 10% of pts, respectively. FLT3, NPM1 and CEPBA mutations were found in 16%, 24%, and 4% of the pts. The mean value of the HCT-CI score was 1.6 (range 0 - 7) at the time of study enrollment and 2.3 (range 0 - 7) at the time of conditioning.The overall response rate assessed at day 15 after start of CLARA was 80% (46% good response defined as less than 10% blast in the bone marrow (BM) and 33% moderate response with at least a marked reduction in BM blasts or BM cellularity and absence of blast in the peripheral blood). Seventeen pts did not respond to CLARA and were subsequently treated off study. Due to early death, three pts were not evaluable for treatment response. Overall, 66% of the pts received HSCT within the trial. Donors were HLA-identical siblings in eight pts (14%), HLA-compatible unrelated donors in 30 pts (55%) and unrelated donors with one mismatch in 17 pts (31%). Treatment success defined as complete remission, CR with incomplete recovery or >95% BM donor chimerism and an absolute neutrophil count >0.5 /nL on day 35 after HSCT was achieved in 62% of the pts. Disease-free survival (DFS) is shown in Figure 1. With a median follow up of 16 months the OS for all enrolled patients at one year is 51% (95% CI, 39% to 63%). [Display omitted] At the time of enrollment, 14% had a related donor and 33% had an unrelated donor. In 46% of the pts donor search was initiated at the time of enrollment. For 7% of pts donor search was not successful. Time from study entry to HSCT was remarkably low with a median of 33 days (range 19 – 116 days). Of note, time interval did not differ between related and unrelated donors (Figure 2). [Display omitted] Day 30 and day 100 mortality, which covered salvage therapy and HSCT, was 9% and 27%, respectively. Six out of seven pts who died within the first 30 days hat refractory AML and thus entered the trial already with a history of long-lasting neutropenia. Liver toxicity was the most frequent adverse event. Fifty percent of the pts had transiently elevated liver enzymes CTCAE grade III considered to be related to clofarabine. Twenty-one patients developed CTCAE grade III – IV sepsis throughout the study treatment. GvHD grade II – IV and III-IV until day 100 after HSCT occurred in 36% and 21% of the pts, respectively. ConclusionsThis intent-to transplant study allows for a realistic estimate for the outcome of elderly pts with relapsed or refractory AML. We demonstrate a high rate of leukemia-control by CLARA. Fast unrelated donor search and work up and conditioning with clofarabine and melphalan in aplasia allowed for a high rate of successful HSCTs. While the long-term results require longer follow-up the overall results are promising. Disclosures:Middeke:Genzyme: Speakers Bureau. Schetelig:Genzyme: Research Funding. Off Label Use: Clofarabine, not approved for AML.

Clofarabine Salvage Therapy Prior to Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed or Refractory AML – Interim Results of the Bridge Trial

AbstractAbstract 2017 BackgroundIn relapsed or refractory AML allogeneic transplantation (HCT) is considered to be the only chance to achieve long-term disease-free survival. However, only about 40% of younger patients with relapsed AML receive allogeneic HCT. A number of factors contribute to this low rate. Among them, a moderate activity of currently available salvage regimens and accumulating toxicity of chemotherapy may prevent from transplantation. Clofarabine is considered to have a favorable risk-benefit ratio in this indication. Therefore, our goal was to study the safety and efficacy of a clofarabine salvage therapy prior to allogeneic HCT (NCT 1295307). Here, we report data from patients of stage I of a two-stage phase II study. Patients and MethodsPatients above the age of 40 with relapsed or refractory AML who were fit for allogeneic HCT were eligible to participate in this multicenter, single-arm study. All patients received at least one cycle of clofarabine 40 mg/m2 followed by intermediate dose cytarabine 1 g/m2 days 1–5 (CLARA). Patients with a donor who exposed at least a reduction of leukemic blasts were scheduled for allogeneic HCT in aplasia after CLARA. Patients without a donor should receive consolidation therapy with CLARA. The conditioning regimen started earliest on day 15 after CLARA and consisted of clofarabine 30 mg/m2 on days -6 to -3 and melphalan 140 mg/m2 on day -2 prior to HCT. GvHD prophylaxis consisted of cyclosporine in combination with MMF. In patients with partially matched unrelated donors the administration of a cumulative dose of 4.5 mg/kg ATG (Genzyme) was recommended. Primary endpoint was treatment success defined as a complete remission (CR, CR(i)) six weeks after completion of therapy. Toxicities were graded according to CTCAE Version 3.0. ResultsTwenty-six patients were enrolled into stage I of this trial. Median age was 60 years (range, 40 to 74 years). Fifty percent of the patients each had refractory or relapsed AML. At early response assessment on day 15 after CLARA-1 13 patients (50%) had less than 10% marrow blasts. Ten patients (38%) showed a reduction in marrow cellularity or blast percentage. Two patients did not respond to CLARA and were subsequently treated off study. One patient died on day 18 after the first cycle from septic multi-organ failure. Twenty-two patients (85%) received allogeneic HCT within this trial. Donors were HLA-identical siblings in 5 patients (23%), HLA-compatible unrelated donors in 11 patients (50%) and partially matched unrelated donors with one mismatch in 6 patients (27%).All 26 patients have been evaluated for the primary endpoint. Sixteen patients had a CR (62%) and 6 patients a CRi (23%) at final response evaluation, all after allogeneic HCT. One patient responded to chemotherapy but needed surgical intervention due to a pulmonary aspergillosis and could not proceed with therapy within the projected timelines and was therefore considered as treatment failure. Liver toxicity was the most frequent adverse event. Seventeen patients (65%) developed grade III liver enzyme elevation considered to be at least possible related to the study drug. Grade IV liver toxicity was observed in 1 patient. Liver injury indicated by elevated transaminases was transient and did not lead to persistent liver damage or hepatic sinusoidal obstruction syndrome. Due to frequently required per-protocol dose reductions of clofarabine prompted by grade III elevations of transaminases the study protocol was amended to a reduced dose of clofarabine 30 mg/m2 in CLARA chemotherapy. Five patients developed grade I/II elevation of creatinine and 2 patients developed renal failure (grade IV) in the context of septic organ failure. Grade I/II hand-foot syndrome occurred in 5 patients. With a maximum follow up of 17 months 14 patients have died (5 patients died after relapse). At present 12 patients are alive, 7 of these are relapse-free, 3 patients are alive with relapse and 2 patients are currently receiving hypomethylating agents for molecular relapse. ConclusionSalvage therapy with CLARA and subsequent conditioning with clofarabine and melphalan prior to allogeneic HCT provides good anti-leukemic activity in patients with relapsed or refractory AML. The complete remission rate of the first 26 patients was evaluated favorably and the trial is currently recruiting to reach the total number of 82 patients. Longer follow up is needed to evaluate relapse-free survival. Disclosures:Middeke:Genzyme: Honoraria. Off Label Use: Clofarabine, not approved for AML. Bornhäuser:Genzyme: Honoraria. Schetelig:Genzyme/Sanofi: Honoraria, Research Funding.

Early Allogeneic Hematopoietic Cell Transplantation in Patients with High Risk AML - Final Results From the Randomized AML 2003 Trial

AbstractAbstract 229▪▪This icon denotes a clinically relevant abstract Background:The optimal timing of hematopoietic cell transplantation (HCT) in AML and its use in risk groups defined by genetic markers or early blast clearance is still under debate. We addressed this question in the AML 2003 study, a large multicenter, randomized, open-label study within the German SAL group. All patients received one cycle of induction therapy (IT) with a 3+7 regimen combining daunorubicin and continuous infusion cytarabine. Upfront cytogenetic and molecular characterization, HLA typing, related donor search and a preliminary search for an unrelated donor were performed for all patients. The subsequent transplant strategy was tailored to the biological risk and donor availability. Patients and Methods:Patients aged 18–60 years were randomly assigned upfront 1:1 to either of two transplant strategies: In the control arm allogeneic HCT was scheduled in first complete remission for patients with intermediate risk cytogenetics and an HLA-identical sibling and for patients with a complex karyotype (CK) and a related or unrelated HLA-compatible unrelated donor. In the experimental arm the indication for allogeneic HCT was extended to patients with an FLT3-ITD allelic ratio >0.8 (mutant/wild type), >10% marrow blasts on day 15 after IT1 and patients with adverse karyotypes, including: −7, −5, del(5q), inv(3q), t(3;3), t(6;9), t(6;11), t(11;19)(q23;p13.1). Furthermore, allogeneic HCT was scheduled at an early time-point, i.e. in aplasia after the first or the second cycle of IT in the experimental arm. Patients without an HLA-compatible donor assigned to the transplant strategy were scheduled for high-dose busulfan and cyclophosphamide followed by autologous SCT. Here, we present the final analysis of this study according to the intent-to-treat principle. Results:Between December, 1, 2003 and November, 26, 2009 1179 patients were randomized between the experimental (N=598) and the control intervention (N=581). The median age was 48 years (range, 18 to 60 years). The distribution of age, ECOG performance status, type of AML, cytogenetic risk groups, NPM1- and FLT3-ITD-mutations, LDH, white blood cell and platelet count was not statistically different between the two treatment arms. However, more males and patients with higher marrow blast counts at diagnosis were randomized to the experimental treatment arm. The median observation time for all patients was 52 months.The hazard ratio of the treatment effect (experimental versus control) was 0.92 (95% CI, 0.75 to 1.14; p=0.45) for primary endpoint overall survival and 0.85 (95% CI, 0.71 to 1.02; p=0.08) for the secondary endpoint event-free survival. Patients in both arms had an excellent long-term overall survival of 50% (95% CI, 46% to 54%) at 5 years after enrollment in the experimental arm and 47% (95% CI, 42% to 51%) in the control arm (see Figure). Across all risk groups the rate of early allogeneic HCT performed per protocol was 22% in the experimental arm and 8% in the control arm. Among patients with high risk cytogenetics this rate was 48% and 17%, respectively. These numbers point at the difficulty to deliver allogeneic HCT within two months after diagnosis of AML in the context of a multicenter trial. However, since HLA-typing and preliminary donor search was done for all patients and allogeneic HCT was standard for relapsed or refractory AML in both arms, the rates of allogeneic HCT as first post remission therapy or after induction failure/relapse were substantially higher than in previous studies and almost equal in the experimental and control arm (63% versus 56%). Conclusions:Although a survival benefit by early allogeneic HCT could not be demonstrated in this large randomized study in newly diagnosed AML, the study treatment resulted in excellent overall survival rates in both arms. Relatively small differences between the per-protocol transplantation rates and crossover effects may partially explain why a benefit of early allogeneic HCT could not be demonstrated. Early awareness of donor availability and the option of allogeneic HCT in patients with primary induction failure or AML relapse resulted in a high overall rate of allogeneic transplantation. This may have contributed to the excellent overall survival in both arms. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Combination of Mycophenolate Mofetil with Cyclosporine A and Methotrexate as Gvhd Prophylaxis In Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 1280Graft-versus-host disease (GVHD) is the dominant complication limiting the efficacy and safety of hematopoietic stem cell transplantation (HSCT), especially from unrelated donors. The most widely used regimen of prophylaxis is the combination of cyclosporine A (CSA)and a short-course of methotrexate (MTX). But the patients receiving grafts from matched unrelated donors still have a 50–80% risk of clinical significant GVHD. Thus, more effective prophylaxis is needed. In this study, we try to evaluate the efficacy and safety of the new GVHD prophylaxis regimen combining mycophenolate mofetil (MMF) with CSA and MTX in unrelated donor allogeneic stem cell transplantation. Between November 1998 and June 2008, 153 patients with a variety of hematologic malignancies were enrolled. There were 102 males and 51 females, median age 26 (range, 8–52) years. Diagnoses were acute myeloid leukemia (n=54), acute lymphoblastic leukemia (n=47),myelodysplastic syndrome (n=8), multiple myeloma (n=1) and chronic myeloid leukemia (n=53). One hundred and eight patients had HLA compatible unrelated donors, 37 patients had single locus-mismatched unrelated donors and 8 patients had 2 loci-mismatched unrelated donors. GVHD prophylaxis consisted of CSA,MTX and MMF. CSA was started on day -7 with the initial dosage of 2.5mg/kg daily, and the dose was adjusted to maintain a whole blood steady-state level of 200–400ng/ml. The dose was tapered during the second to third month post-transplant depending on GVHD status. MTX was given at a dosage of 10mg on days+1, +3 and +6. MMF was administered at an oral dose of 500mg daily from day 0 to day +100. The cumulative incidence of grades II-IV aGVHD and grades III-IV aGVHD for all patients were 43.9% and 17.9% respectively for entire group. The cumulative incidence of grades II-IV aGVHD for patients who had HLA-matched donors and mismatched donors were 40.2% and 51.9% respectively (P=0.079). The cumulative incidence of grades III-IV aGVHD for patients who had HLA-matched donors and mismatched donors were 14.0% and 26.9% respectively (P=0.026). The cumulative incidence of cGVHD was 41.4%, with 19.3% extensive cGVHD. At 3 years, the incidence of relapse for entire group was 24.0%. The cumulative incidence of transplant-related mortality at 100 days and 3 years were 12.5% and 34.9%, respectively. The probabilities of overall survival at 2 years and 5 years were 59.2% and 50.2%, respectively. The probabilities of disease-free survival at 2 years and 5 years were 56.3% and 46.7%, respectively. From these results, we conclude that the combination of MMF with CSA and MTX is an effective prophylaxis regimen for acute and chronic GVHD in unrelated donor allogeneic stem cell transplantation without increasing the risk of relapse. Disclosures:No relevant conflicts of interest to declare.

C-reactive protein levels before reduced-intensity conditioning predict outcome after allogeneic stem cell transplantation

The prognostic value of CRP levels before conditioning for allogeneic stem-cell transplantation (ASCT) was evaluated. Reduced-intensity conditioning (RIC) was given to 205 patients and conventional myeloablative conditioning (MAC) to 299 patients. Most patients had an HLA-compatible related or unrelated donor. There were 287 males and 216 females, median age 36 (1-69) years. Most patients received peripheral blood stem cells. Increased CRP levels (>10 mg/L) were detected in 129 patients (26%). Overall survival (OS) and transplant-related mortality (TRM) were worse for RIC patients with elevated CRP (67 vs. 43%, p = 0.005, and 16 vs. 30%, p = 0.036) while no difference was seen in MAC patients. An infection at the start of conditioning was seen in 27 RIC patients. We identified a subgroup of patients with an infection and elevated CRP (n = 16) and these patients had the worst outcome. In multivariate analysis, both infection and elevated CRP was the strongest factor associated with OS (HR 3.27, p < 0.001) and TRM (HR 4.35, p < 0.001). No correlation between any outcome variable and CRP was seen in MAC-treated patients. CRP may be a good prognostic factor for outcome after RIC and ASCT. It should be analyzed before conditioning, especially in patients with coexisting infection since patients with increased CRP and infection seem to have a very poor outcome after ASCT.

Mobilized Peripheral Blood Stem Cells (PBSC) Compared with Bone Marrow (BM) as the Stem Cell Source for Unrelated Donor Allogeneic Transplantation with Reduced Intensity Conditioning (RIC-alloSCT) in Patients with Acute Myeloid Leukemia (AML) in Complete Remission (CR): a Retrospective Analysis From the ALWP of EBMT.

Abstract 527RIC-alloSCT is being increasingly used for AML patients with high comorbidities not eligible for standard myeloablative conditioning. Few published data advocate the use of PBSC instead of BM in RIC in the HLA identical sibling setting, however only scarce data is availabel in RIC-alloSCT using unrelated donors. Moreover, sometimes volunteer donors are reluctant to use G-CSF. Therefore, we compared outcomes of PBSC vs. BM RIC-alloSCT, using the EBMT ALWP data set. Between 2000 and 2008, 803 patients with AML in CR underwent RIC-alloSCT from HLA compatible unrelated donors with PBSC (690) or BM (113) grafts. Recipient‘s age was higher in the PBSC vs. BM groups 57y (range, 19-77) and 52y (range, 18-76), respectively (P<0.0001), while gender was comparable between the 2 groups. Leukemia features were also comparable between the PBSC vs. BM groups, such as WBC at diagnosis (10.4×109/L vs. 8.6×109/L), cytogenetics–good risk (6.7% vs. 9.6%), intermediate risk (73.9% vs. 75%) and poor risk (19.4% vs. 15.4%) as well as for FAB classification. Disease status at RIC-alloSCT was not statistically different between the 2 cohorts: in the BM group 57% were in first CR and 43% in second CR compared to 64% and 36% in the PBSC group, respectively (p=0.13). Time from diagnosis to transplant was 239d in PBSC group vs. 332d in the BM group (P<0.0001) and low-dose TBI-based conditioning was more frequently used in PBSC (33.2%) compared to 6.2% in the BM group (P<0.0001). Donor gender and CMV serostatus were not statistically different in both groups. There was a difference in year of transplant as it was 2006 (2000-2008) vs. 2005 (2000-2008) for the PBSC vs. BM RIC-alloSCT (P<0.001). Results: Engraftment was achieved in 95% of the patients in both groups. Acute GVHD grade > II was significantly higher in the PBSC group, 28% compared to 12% in BM group, (P<0.0001). Similarly, chronic GVHD (2y) was higher in the PBSC with 55±3% vs. 48±9% in the BM group, respectively (P=0.05). The 2-year probabilities of LFS and relapse incidence were 44±3% and 38±3% for the PBSC transplants in comparison to 42±6% and 51±7%, for the BM group (NS), while, non relapsed mortality was significantly higher for the PBSC vs. BM group, 29±3% vs. 14±5%, respectively (P=0.007). In multivariate analysis, after statistical adjustments of differences, the PBSC group was associated with a higher incidence of aGVHD (II-IV) (HR=3.2, p=0.01), higher NRM (HR=2.6, p=0.005), a trend of decreased relapse incidence (HR 1.47, p=0.06) and no statistical difference of LFS between the two groups (p=0.62). In conclusion: 1) The vast majority (86%) of the unrelated RIC - alloSCT for AML performed in Europe are from PBSC rather than from BM grafts. 2) Our results indicate significantly higher incidence of acute GVHD and NRM, but not statistically different LFS comparing unrelated PBSC to BM grafts following RIC conditioning. Therefore, there is no disadvantage for using unrelated BM rather than unrelated PBSC grafts in the RIC-alloSCT setting. Whether PBSC should be preferred in advanced phase of the disease, where outcome is dominated by relapse incidence, need to be further investigated. Disclosures:No relevant conflicts of interest to declare.