Bone Marrow Cell Therapy Research Articles

Abstract 16655: Bone Marrow Cell Therapy in Patients With Ischemic Heart Disease: A Meta-analysis of Randomized Controlled Trials Using Cardiac MRI

Introduction: The results from clinical trials of bone marrow cell (BMC) therapy in ischemic heart disease (IHD) have been discordant with regard to left ventricular (LV) functional improvement. This discrepancy has been attributed, in part, to the use of dissimilar cardiac imaging modalities. MRI is the gold standard for assessment of cardiac structure/function. Hypothesis: We hypothesized that BMC therapy will improve LV parameters in patients with IHD when assessed by cardiac MRI. Methods: We performed a systematic review and meta-analysis of data from randomized controlled trials (RCTs) of BMC therapy in patients with IHD that used cardiac MRI. Database searches through May 30, 2015 identified 27 eligible RCTs (enrolling 1826 patients). The MRI data on LV ejection fraction (EF), infarct size, LV end-systolic volume (LVESV), and LV end-diastolic volume (LVEDV) were analyzed with random-effects meta-analysis. Clinical outcomes were analyzed using Peto odds ratio (OR). Results: Compared with standard therapy, BMC therapy improved LVEF (1.62%; 95% confidence interval [CI]: 0.49 to 2.75; P=0.005) and reduced LVESV (-2.00 ml; 95% CI: -3.19 to -0.82; P=0.0009). The improvement in LVEF was similar in patients with acute myocardial infarction (MI) and chronic IHD. Perhaps more importantly, BMC therapy was associated with reduced incidence of recurrent MI (OR: 0.39; 95% CI: 0.20 to 0.78; P=0.007) along with substantial improvement in other outcome parameters, including mortality (Table). However, these changes did not reach statistical significance perhaps due to smaller patient numbers. Conclusions: These results from meta-analysis of RCTs using cardiac MRI indicate that BMC therapy improves LV function and outcomes in patients with IHD. These data may help resolve the controversy regarding whether the reported benefits of BMC therapy are dependent on the selection of imaging modalities.

Abstract 16619: Bone Marrow Cell Therapy Improves Left Ventricular Function And Survival in Patients With Chronic Ischemic Heart Disease and Cardiomyopathy

Introduction: Results from randomized controlled trials (RCTs) of bone marrow cell (BMC) therapy for cardiac repair have been discordant. The true impact of BMC therapy in patients with chronic ischemic heart disease (CIHD) and ischemic heart failure remain unclear. Hypothesis: We hypothesized that BMC injection would improve clinical outcomes and left ventricular (LV) parameters in patients with CIHD. Methods: We performed a systematic review and meta-analysis of data from RCTs of BMC therapy on LV ejection fraction (LVEF), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), infarct scar size, and clinical outcomes in patients with CIHD. Database searches based on specified criteria identified 15 eligible RCTs (enrolling 648 CIHD patients). Changes in predefined parameters were analyzed with random-effects meta-analysis. Peto odds ratio (OR) was calculated for clinical outcomes. Results: Compared with standard therapy, BMC transplantation improved LVEF (3.84%; 95% confidence interval [CI], 2.30 to 5.38; P<0.00001), reduced scar size (-5.90%; 95% CI, -8.03 to -3.78; P<0.00001) and LVESV (-10.37 ml; 95% CI, (-18.56 to -2.18; P=0.01). Reduction in LVEDV (-1.84 ml; 95% CI, -9.13 to 5.46; P=0.62) was not significant. The improvement in LVEF in BMC-treated patients was also significant (1.78%; 95% CI: 0.63 to 2.93; P=0.002) in a separate analysis of RCTs that used MRI. Importantly, BMC therapy reduced all-cause mortality (OR: 0.35; 95% CI 0.16 to 0.73; P=0.005) and incidence of cerebrovascular accident (CVA) (OR: 0.07; 95% CI, 0.01 to 0.55; P=0.01) and tended to reduce the incidence of heart failure (OR: 0.36; 95% CI 0.11 to 1.14; P=0.08) in patients with CIHD (Table). Conclusions: BMC therapy improves LVEF, LVESV, and infarct scar size in patients with CIHD. The improvement in LVEF was also confirmed in meta-analysis of RCTs using MRI. Importantly, these numerically small benefits translated into improved clinical outcomes in BMC-treated CIHD patients.

Abstract 17412: Paracrine Role of B Lymphocytes in Successful Bone Marrow Cell Therapy for Myocardial Infarction

Introduction: Treatment of myocardial infarction (MI) with bone marrow cells (BMCs) or cell-free BMC lysate substantially improves post-MI cardiac function in rodent experiments. However, clinical trials of BMC therapy have been less successful. While most mouse experiments use young healthy BMC donors, MI patients undergoing autologous cell therapy (i.e., receiving their own BMCs) are older and are post-MI. We have previously demonstrated that BMCs from aged and post-MI donor mice are therapeutically impaired, that donor MI induces inflammation leading to changes in BMC composition, and that BMCs from aged or post-MI mice have reduced levels of B cells, which reportedly can be a therapeutic BMC subpopulation. We recently observed that partial depletion of B cells from young healthy donor BMCs reduces the BMCs’ therapeutic effect, mimicking the effects of donor age or MI. Hypothesis: B cells play a crucial role in BMC therapy for MI, and B cell lysate is also therapeutic. Methods: We induced permanent coronary artery ligation MI, and implanted purified CD19+ bone marrow B cells from young healthy donors into the recipient infarct border zone 3 days post-MI via ultrasound guidance. CD3ε+ T cells and vehicle (HBSS) were injected as negative controls. A similar experiment was carried out with B cell lysate and T cell lysate. Results: In all groups, recipient left ventricular ejection fraction (EF) declined uniformly from baseline to day 2 post-MI, before cell injection. Injection of B cells significantly improved day 28 EF (p<.0005 adjusted for multiple comparisons). In contrast, T cells provided little or no benefit relative to HBSS. Notably, B cell lysate, but not T cell lysate, increased EF comparably to intact B cells. *p<.05 in figure. Conclusions: Bone marrow B cells play a crucial role in BMC therapy for MI via a paracrine mechanism. Reduction of bone marrow B cells by age or MI may explain why autologous BMC therapy in patients has not matched the success of rodent experiments.

Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS): study protocol for a randomised controlled trial.

BackgroundWe have recently completed an evaluation of the safety and feasibility of intravenous delivery of autologous bone marrow in patients with progressive multiple sclerosis (MS). The possibility of repair was suggested by improvement in the neurophysiological secondary outcome measure seen in all participants. The current study will examine the efficacy of intravenous delivery of autologous marrow in progressive MS. Laboratory studies performed in parallel with the clinical trial will further investigate the biology of bone marrow-derived stem cell infusion in MS, including mechanisms underlying repair.Methods/designA prospective, randomised, double-blind, placebo-controlled, stepped wedge design will be employed at a single centre (Bristol, UK). Eighty patients with progressive MS will be recruited; 60 will have secondary progressive disease (SPMS) but a subset (n = 20) will have primary progressive disease (PPMS). Participants will be randomised to either early or late (1 year) intravenous infusion of autologous, unfractionated bone marrow. The placebo intervention is infusion of autologous blood. The primary outcome measure is global evoked potential derived from multimodal evoked potentials. Secondary outcome measures include adverse event reporting, clinical (EDSS and MSFC) and self-assessment (MSIS-29) rating scales, optical coherence tomography (OCT) as well as brain and spine MRI. Participants will be followed up for a further year following the final intervention. Outcomes will be analysed on an intention-to-treat basis.DiscussionAssessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS) is the first randomised, placebo-controlled trial of non-myeloablative autologous bone marrow-derived stem cell therapy in MS. It will determine whether bone marrow cell therapy can, as was suggested by the phase I safety study, improve conduction in multiple central nervous system pathways affected in progressive MS. Furthermore, laboratory studies performed in parallel with the clinical trial will inform our understanding of the cellular pharmacodynamics of bone marrow infusion in MS patients and the mechanisms underlying cell therapy.Trial RegistrationISRCTN27232902 Registration date 11/09/2012. NCT01815632 Registration date 19/03/2013

Reduction of healthcare utilization after bone marrow cell therapy for refractory angina pectoris

☆ Funding: This work was supported by the Transla [TeRM-Smart Mix SSM06004], the BioMedical Materials Heart Foundation [cell therapy program: Translational Department of Cardiology receives unrestricted research Medtronic and Biotronik. ☆☆ Disclosures: None. ⁎ Corresponding author at: Department of Cardiolo Center, Post Office Box 9600, 2300 RC Leiden, The Nether Leiden, The Netherlands. E-mail address: d.e.atsma@lumc.nl (D.E. Atsma). 1 This author takes responsibility for all aspects of the re of the data presented and their discussed interpretation.

Adult Bone Marrow Cell Therapy for Ischemic Heart Disease: Evidence and Insights From Randomized Controlled Trials.

Notwithstanding the uncertainties about the outcomes of bone marrow cell (BMC) therapy for heart repair, further insights are critically needed to improve this promising approach. To delineate the true effect of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials. Database searches through August 2014 identified 48 eligible randomized controlled trials (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction, infarct size, LV end-systolic volume, and LV end-diastolic volume were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LV ejection fraction (2.92%; 95% confidence interval, 1.91-3.92; P<0.00001), reduced infarct size (-2.25%; 95% confidence interval, -3.55 to -0.95; P=0.0007) and LV end-systolic volume (-6.37 mL; 95% confidence interval, -8.95 to -3.80; P<0.00001), and tended to reduce LV end-diastolic volume (-2.26 mL; 95% confidence interval, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in reporting of outcomes. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LV ejection fraction improved in BMC-treated patients when assessed by magnetic resonance imaging. Early (<48 hours) BMC injection after myocardial Infarction was more effective in reducing infarct size, whereas BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up, albeit with differences between acute myocardial Infarction and chronic ischemic heart disease subgroups. Transplantation of adult BMCs improves LV ejection fraction, reduces infarct size, and ameliorates remodeling in patients with ischemic heart disease. These effects are upheld in the analyses of studies using magnetic resonance imaging and also after excluding studies with discrepant reporting of outcomes. BMC transplantation may also reduce the incidence of death, recurrent myocardial Infarction, ventricular arrhythmia, and cerebrovascular accident during follow-up.

Management of Myelodysplastic Syndrome Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation: A Study by the French Society of Bone Marrow Transplantation and CellTherapies.

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P= .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P= .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT.

SS21. Long-Term Follow-Up of Autologous Bone Marrow Cell Therapy: A Randomized Controlled Double-Blind Study for No-Option CLI

SS21. Long-Term Follow-Up of Autologous Bone Marrow Cell Therapy: A Randomized Controlled Double-Blind Study for No-Option CLI

Relationship between perioperative cardiovascular risk factors and bone marrow cells from patients undergoing coronary artery bypass grafting surgery.

Cell therapy through the implantation of autologous bone marrow cells has long been used in clinical trials for the treatment of ischemic heart diseases. However, as the outcomes of cell implantation vary among patients, risk factors that might influence the level and function of bone marrow progenitor cells should be determined, to identify patients who would benefit the most from this treatment. We collected clinical and laboratory data from 44 patients scheduled to undergo sternotomy for coronary artery bypass grafting (CABG). Bone marrow was aspirated from the sternum during the operation, and bone marrow mononuclear cells (BMMNCs) were isolated through density centrifugation. A negative correlation was observed between the number of BMMNCs and age (N = 44, r = -0.788, P = 0.001). The level of CD34+ cells in BMMNCs was 0.94 ± 0.39%, CD133+ cells 0.46 ± 0.28%, and CD34+CD133+ cells 0.53 ± 0.26%. The levels of CD34+ and CD133+ cells in diabetic patients were significantly lower than those in nondiabetic patients. Female gender, advanced age, and poor heart function were related with reduced progenitor cell clonogenic function. A positive correlation was observed between the level of CD34+ cells and BMMNC migration ability. Aging and diabetes were the major risk factors that influence the level and function of bone marrow resident progenitor cells in patients with coronary heart disease undergoing CABG. Further study is needed to determine whether these two factors can influence the outcome of bone marrow cell therapy for ischemic heart disease.

Autologous Stem Cell Transplantation (ASCT) for Patients Aged 60 Years or Older with Classical Hodgkin Lymphoma : A Retrospective Analysis from the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Background: Twenty percent of classical Hodgkin Lymphoma (cHL) patients are aged 60 years or older. Their survival rate is inferior to that of younger patients for several reasons including lower delivery of standard chemotherapy and toxicity excess. For relapsed or refractory (R/R) cHL young patients, autologous stem cell transplantation (ASCT) is a standard of care after salvage chemotherapy. However, little is known regarding the outcome of R/R cHL in elderly patients (≥60 years) receiving ASCT.Method: The current report retrospectively analyzed the outcome of all consecutive patients aged 60 years or older with the diagnosis of R/R cHL who were transplanted between 1992 and 2013 and who were reported to the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) registry. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all SFGM-TC centers. This study was approved by the scientific committee of the SFGM-TC and is in accordance with Helsinki declaration for clinical research. Of note, specific study questionnaires were sent to transplant centers to obtain comprehensive, updated data.Results: One hundred and twenty patients met these criteria. Ninety-one patients (63M/28F) with documented data from 28 transplant centers were analyzed. Median age was 63 years at transplant (range 60-75). At diagnosis, 64 patients had advanced stage cHL, 46 had B symptoms and 6 had poor performance status (ECOG 2). Thirty-four patients had primary refractory disease, and 22 patients relapsed within the first year after first CR. The median number of salvage chemotherapy regimens was 2 (range 1-4). Most of the patients showed disease sensitivity to salvage treatment with 52 patients transplanted in CR, 5 patients in CRu, 30 patients in PR and 1 patient transplanted with progressive disease. The most frequently used conditioning regimen consisted of BEAM chemotherapy (93%) (Carmustine 300 mg/m2 d-6, Etoposide 100 mg/m2 Q12H d -5 to -2, Cytarabine 200 mg/m2 IV Q12H d-5 to -2, Melphalan 140 mg/m2 d -1). The median number of CD34 peripheral blood stem cells was 4.2 106 cells/kg (range 0.9-17.8). The median duration of hospitalization was 22 days (8-49). The median time to achieve neutrophil count >1x109/L and platelet count > 20x109/L were 11 days (range 8-104) and 13 days (range 7-115), respectively. Grade 3-4 toxicities occurred in 24 patients (mucositis: 13, sepsis: 3, interstitial pneumonia: 2, diarrhea: 2, heart failure: 2, multiorgan failure (MOF): 1, unspecified case: 1. With a median follow-up of 32 months (range 1-185), the 6-year estimate of OS was 64% (95% CI 51-75). In univariate analysis, none of the usual prognostic factors (gender, age ≥ 65, disease status before transplant, CD34+ cells count, time to relapse < 1 year, disease stage at relapse, Hb level) significantly influenced OS. At last follow-up, 13 patients died: 5 from toxicity (1 MOF, 2 interstitial pneumonia, 1 heart failure and 1 invasive pulmonary aspergillosis), 4 from disease progression, and 4 from unspecified causes.Conclusion: This retrospective study with long term follow-up, despite its limitations, suggests that in selected elderly patients ASCT is a valid treatment option for chemosensitive R/R cHL patients, with an acceptable rate of toxicity warranting further investigations in the era of novel agents such as brentuximab. DisclosuresBrice:Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Honoraria, Research Funding; Roche: Honoraria.

Outcome after Relapse or Progression Following First Allogeneic Hematopoietic Stem Cell Transplantation in Children with Acute Leukemia. a Retrospective Analysis from the French Society of Bone Marrow Transplantation and Cell Therapies

BackgroundHematopoietic stem cell transplantation (HSCT) has contributed to improve outcome for pediatric patients with acute leukemia (AL). However, post-transplantation relapse is still associated with a dismal prognosis and its optimal treatment remains unclear. Therapeutic strategies may vary according to the relapse delay, as well as centers and child’s specific requirements.AimWe aimed to compare patients’ related factors and treatment strategy, in case of relapse or progression post-allogeneic HSCT in children with acute leukemia in a recent ten-year period.MethodsWe analysed all consecutive 334 children (<18 years, 134 Females) who received a first allogeneic HSCT for ALL or AML from January 2000 to December 2009 and experienced a relapse or progression thereafter. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by the 33 centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) who participated to this study. The primary endpoint was overall survival (OS) after diagnosis of relapse or progression post first HSCT whatever the treatment post relapse was. Secondary endpoints included OS after a) second HSCT, b) chemotherapy alone, c) donor lymphocytes infusion (DLI) d) chemotherapy followed by DLI or e) supportive and palliative care. We also assessed prognostic risk factors for survival after failure post-HSCT.Results279 patients (110 females and 169 males) with a median age of 8.8 years at transplantation (range: 0.52-17.99) were included. Diseases were 149 ALL (B-cell phenotype, n=120; T-cell phenotype, n=29), 122 AML and 8 biphenotypic AL. At transplantation, 233 patients were in complete remission (CR) (CR1 n=121, CR2 n=94, CR3 n=18) while 46 had a cytologically detectable disease. Donors were matched related siblings (36%), mismatched related (4%), matched unrelated (18%), mismatched unrelated (24%), unrelated without precision (16%) or syngenic (2%). Stem cell source was bone marrow, peripheral stem cells, umbilical cord blood in 65%, 12%, 23% of cases, respectively. Median time from diagnosis to first HSCT was 263 days. 91% (n=254) children received myeloablative conditioning and 9% (n=25) received reduced intensity conditioning regimens. Total body irradiation (TBI) was performed in 153 children. Acute GVHD after first HSCT occurred in 157 patients (grade I n= 62 grade II to IV n= 94). The median delay from first HSCT to relapse/progression was 182 days. The treatments for relapse after first HSCT consisted in chemotherapy alone (n=103), chemotherapy followed by second HSCT (n=70), supportive and palliative care (n=66), combination of chemotherapy and DLI (n=27), or isolated reinfusion of donor lymphocytes (DLI) (n=13).At the time of analysis 40 patients (12%) were alive with a median follow up of 1315 days (range 58;4182). The median OS duration after relapse was 149 days among the 334 patients. The median survival duration in days according to therapy was as follows [confidence interval]: DLI after chemotherapy = 407 [156;658], Second allograft: 391 [264;518], chemotherapy: 180 [121;239], DLI alone: 140 [10;270], Palliative care: 43 [33;53] (see Figure 1). A Cox model analysis on 260 patients with complete files showed the impact of the following factors on survival, when comparing to the best line of treatment, ie chemotherapy+DLI; treatment by chemotherapy alone (HR 2.05, p=.008), palliative care (HR=5,7, p<.001), first transplant performed in complete remission (HR= 1.57, p=.031). The time interval from transplantation to relapse was also associated with prognosis: when comparing to relapses occuring within the first 90 days, day 90-179, day 180-269, and >270 days yielded hazard ratios of respectively .549, .479 and .293 (p <.003).There was no impact on outcome from the following variables: gender, age at transplant, leukemia subtype, type of conditioning, conditioning with TBI , GVHD occurrence after the first transplant, stem cell source.ConclusionDespite evident limitations due to the retrospective setting of our analysis, best treatment consisted in second transplantation or the combination of chemotherapy plus DLI, both yielded similar long-term results. Those results favor the use of immune based strategies when possible in this particular situation of relapse post-HSCT, which should be evaluated in prospective trials. [Display omitted] DisclosuresMohty:Gentium S.p.A./Jazz Pharmaceuticals Inc.: Honoraria, Research Funding.

Unrelated Alternative Donor Transplants for Severe Acquired Aplastic Anemia: A 12-Year Retrospective Study from the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

In the absence of a matched sibling donor for patients with severe aplastic anemia (SAA), allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from an HLA-matched unrelated donor (UD) is considered after immune suppressive therapy (IST) failure. Outcome after UD Allo-HSCT for SAA has significantly improved in the last 2 decades because of optimization of HLA typing, as well as better conditioning regimens and improved GVHD prophylaxis (Maury Haematologica 2007; Bacigalupo Haematologica 2010). However, the age limit, the impact of extensive HLA typing (12 loci) as well as the best timing for UD Allo-HSCT remain unclear. We thus analyzed all patients in France who received a first Allo-HSCT for idiopathic SAA from a UD between 2000 and 2012. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). The French national ethics board (CCTIRS) approved this study. Written informed consent was obtained from all patients before Allo-HSCT.One-hundred and thirty-nine consecutive patients (64 male (46%)) were included. Median age was 23 years (range: 1-66). Most patients (81%) received in vivo T-cell depletion using antithymocyte globulins or alemtuzumab. Total body irradiation was used in 64 patients (46%), using low dose in 58 cases (91%). GVHD prophylaxis combined Cyclosporine A and methotrexate in 68% of cases. Respectively 113 (81%) patients and 26 (19%) patients were transplanted using a 10/10 and a 9/10 HLA-matched UD (according to HLA A, B, C, DRB1 and DQB1 allelic matching). Ten patients (7%) experienced primary graft failure. Forty-eight patients developed grade II-IV acute GVHD, leading to a day-100 cumulative incidence of 35%. The cumulative incidence of chronic GVHD was 24% at 4 years (extensive GVHD, 8%) with no specific risk factor identified. With a median follow-up of 51 months, the 4-year overall survival (OS) was 66% for the whole cohort. In multivariate analyses, worst OS was observed for patients transplanted before 2006 (HR=2.45 [1.23-4.88]; p=0.011, Figure 1A), with a CD34+ cell dose < 4 x 106/kg (HR=2.62 [1.31-5.25]; p=0.006), with time from diagnosis to Allo-HSCT > 12 months (HR=2.16 [1.02-4.60]; p=0.046) and who received a 9/10 matched UD (HR=2.27 [1.05-4.91]; p=0.038). Of note, there was a trend for higher mortality in patients older than 40 years of age (HR=1.97 [0.95-4.09]; p=0.069). There was no difference in OS according to conditioning regimen or GVHD prophylaxis. Ninety-eight out of 139 patients had extensive HLA typing on 12 loci (HLA A, B, C, DRB1, DQB1 and DPB1), respectively 82 and 16 patients from the 10/10 and 9/10 HLA-matched groups. Zero, 1 and 2 DPB1 matched alleles were found in 36 (37%), 52 (53%) and 10 (10%) patients, respectively. Of note, we found no difference in 4-year OS according to DPB1 matching among the 82 evaluable 10/10 HLA-matched patients (0 (n=27) vs. 1 or 2 matched DPB1 alleles (n=55): 74% vs. 66%, p=0.466). However, patients transplanted with a 9/10 HLA-matched donor with no matched DPB1 allele reached a significantly lower 4-year OS (0 (n=9) vs. 1 or 2 matched DPB1 alleles (n=7): 22% vs. 86%, p = 0.029, Figure 1B).In conclusion, outcome after UD Allo-HSCT for idiopathic SAA continues to improve with best results seen after 2005. In the presence of a 10/10 matched UD (allelic level), patients less than 40 years of age should be transplanted as quickly as possible if refractory to IST, at least in the first year after the time of diagnosis. Given the excellent OS in the recent period and the particularly low rate of chronic GVHD, Allo-HSCT could be discussed as front line therapy in selected young patients with SAA for whom a 10/10 UD is readily available in the absence of a matched family donor. Moreover, in the absence of a 10/10 HLA-matched UD, Allo-HSCT from a 9/10 HLA-matched UD in the presence of 1 or 2 matched DPB1 alleles is promising and merits further evaluation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

HLA-Matched Related Donor Hematopoietic Cell Transplantation in Patients with Fanconi Anemia Conditioned with a Combination of Cyclophosphamide and Fludarabine : A Study on Behalf of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Background.Fanconi anemia (FA) is a rare, phenotypically heterogeneous, inherited disorder clinically characterized by congenital abnormalities, progressive bone marrow failure (BMF) and a predisposition to develop malignancies. Hematopoietic stem cell transplantation (HSCT) is the only curative option for FA patients. However, finding the best conditioning regimen is still challenging for clinicians. To reduce toxicities, we used progressively lower doses of cyclophosphamide (CY) for conditioning through non-irradiation based regimens. A reduced conditioning regimen based on CY 60mg/kg alone was proposed by Bomfim et al (BBMT, 2007). Survival rates were excellent but some patients experienced primary (n=1) or late (n=4) graft failure (11% of the patients). Mucositis was a major problem as 25 patients (60%) presented grade 3 / 4 mucositis. The rate of Chronic graft versus host disease (GvHD) was 29%. We hypothesized that tapering the dose of CY to 40mg/Kg and adding fludarabine (FLU) at 90mg/m2 might improve engraftment, decrease GvHD rates and eventually improve overall toxicity in FA patients transplanted with HLA matched siblings.Method.In 2004, the French reference centre for aplastic anemia and the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) recommended to use FLU 90mg/m2 (30mg/m2 days -4, -3, -2) and CY 40mg/kg (10mg/kg days -5, -4, -3, -2) for FA patients transplanted from matched family donor. Indication for transplantation was based on hematological complications (transfusions and/or infections). FA patients with morphologic signs of clonal evolution (myelodysplastic syndrome or acute myeloid leukemia) were excluded. All patients in France who received a first Allo-HSCT for FA from a matched related donor between October 2004 and January 2013 using this approach were analyzed (n=20). Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all SFGM-TC centres. All patients received uromitexan. Ciclosporin A and micophenolate mofetil were used as GVHD prophylaxis. Six patients received an in vivo T cell depletion using antithymocyte globuline because of local policy at their centre. The guidelines were approved by Saint-Louis hospital ethical committee.Results.The median age at transplant was 9 years (range: 6-19). Stem cell source was bone marrow in 16 cases and matched related cord blood in the remaining transplants. None of the patients received peripheral blood stem cells. All patients had severe or moderate BMF (median hemoglobin: 8.9g/dl, median platelets: 31 103/ul, median neutrophils: 0.88 103/ul) at time of transplant. Two patients had chromosomal abnormalities (47,XX,i(1)(q10)[10]/48,idem,+8[3] and 47,XX,+der(1;3)(q10;q10)[14]/46,XX[6]); however, none of them developed overt myelodysplasia/leukemia before transplant. Patients belonged to complementation groups FANC-A (n=17) and FANC-G (n=2). Transplantation was performed within a median of 30 months from FA diagnosis (range: 7-143). A median of 3.8. 108 nucleated marrow cells were infused (range: 0,65-8,97).Within a median follow up of 2 years (range: 0.2-7.4), overall survival was 95% (figure 1). Only one patient with an atypical form of FA associated with severe immunodeficiency prior to transplant died subsequently due to uncontrolled cerebral toxoplasmosis. Engraftment rate was 100% with a median time to neutrophils and platelets recovery of 16.5 (11-28) and 15 (4-29) days, respectively. No grade 3/4 regimen related toxicity was observed and only 1 patient experienced mucositis (grade 2) using this conditioning regimen. Total acute GvHD grade 3 / 4 was only observed in 3 patients (15%) and chronic GvHD was extensive in 2 patients (10%) and limited in 3 patients (15%). Median alive patients karnofsky scored 100% (range 90 – 100%). No secondary malignancy was observed in our cohort so far.Conclusion.The combination of low dose CY (40mg/Kg) plus FLU (90mg/m2) in HLA-matched donor HSCT in patients with FA resulted in an excellent engraftment rate (100%) with no secondary graft failure, low rates of acute and chronic GvHD, low rates of regimen related toxicity, eventually resulting in an excellent overall survival (95% at 2 years). A longer follow-up in this cohort is needed to confirm such excellent results long-term, namely the continued absence of secondary cancer. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Antithymocyte Globulins on Patient Outcome after Myeloablative Bone Marrow Stem Cell Transplantation from HLA 10/10-Matched Unrelated Donor: A Report from the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Background: A recent prospective study (Socie & al Blood 2011) demonstrated that the addition of antithymocyte globulins (ATG) to prophylaxis for graft versus host disease (GVHD) in the setting of standard myeloablative conditioning (MAC) regimen matched unrelated donor (UD) allogeneic stem cell transplantation (HSCT) resulted in a decrease in incidence of chronic GVHD without an increase of relapse or non-relapse mortality. However, stem cell source was mostly peripheral blood stem cells (PBSC) and patients (pts) were compatible at HLA-A, HLA-B, HLA-DRB1 and HLA-DQB1 (eight out of eight alleles). A retrospective study using the same setting (Mohty & al Leukemia 2012) found very similar results with donor/recipient pairs matched at 10 loci (ten out of ten alleles). However, one third of the pts received PBSC as stem cells source and 20% of the pts were transplanted with a mismatch donor (9 out of 10 alleles). We thus conducted this study to assess the impact of ATG in pts with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) transplanted with MAC using bone marrow only (BM) from matched 10/10 UD.Patients and methods: We includedall consecutive pts older than 18 years who received a first HSCT in France for AML or MDS with BM from a matched 10/10 UD after a standard conditioning regimen (fractionated total body irradiation (TBI)-Cyclophosphamide(Cy), n=106 or Endoxan-Cy, n=91) between June 2000 and June 2012. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). This study was approved by the scientific committee of the SFGM-TC.Results: A total of 197 adult pts met the criteria and were analyzed (165 AML (84%) and 35 MDS). 54 (27%) pts received ATG in the conditioning regimen whereas 143 (73%) did not. Median follow up was of 20.3 months [0.4-156]. Both groups (with or without ATG) were well balanced except for the number of CD34+ cells infused (higher in the ATG group: 3.07x106/kg [0.7-13] vs 2.71x106/kg [0.6-89] for none ATG group (p=0.03)) and GvHD prophylaxis (more likely cyclosporine plus methotrexate with ATG (94%) vs 84% without, p=0.05).The probability of acute GvHD grade II-IV was similar between both groups: 41.3% with ATG vs 49.6% without, p=0.2. Incidence rate of severe acute GVHD grade III-IV at day 100 tended to be lower in the ATG group as compared with the none ATG group (20.3% vs 9.5%, respectively, p=0.052). The cumulative incidence (CI) of chronic GVHD at 2 years was 42% in the ATG group vs 28% in the none ATG group and 37% vs 44% at 4 years, respectively (p=0.18). The probability of extensive chronic GVHD at 2 years was identical between both groups (12% with ATG vs 16% without, p=0.95).CI of non-relapse related mortality (NRM), relapse as well as disease free survival (DFS) and overall survival (OS) were similar between the 2 groups (Table 1). In multivariate analysis, advanced disease status was the only parameter associated with decreased DFS (HR 0.37, 95% CI [0.19-0.70], p=0 .02) and OS (HR 0,41, 95% CI [0,24;0,71], p<0.01). During the study, 106 pts died (28 pts (52%) in the ATG group and 78 in the none ATG group (53%)). No difference was observed in terms of cause of death (detailed in Table 2) between the two groups, relapse accounting for half the causes of in both groups (47%).Conclusion:The addition of ATG to MAC regimen in pts with AML or MDS transplanted with BM from matched 10/10 resulted in similar outcomes in terms of NRM, relapse as well as DFS and OS. Despite the limitation due to the retrospective setting of our study, we did not find any obvious benefit for adding ATG to the conditioning regimen in this setting. Prospective studies are needed to firmly answer to this question and notably to better assess a possible benefit in terms of quality of life in the ATG group.Table 1:2-years cumulative incidence of NRM, relapse, DFS and OSOutcomesATG group % [95% CI]Non ATG group % [95% CI]p valueNRM21 [15-27]23 [19-27]0.90Relapse32 [25-39]31 [27-35]0.83DFS46.9 [39.9-53.9]46.7[39.7-53.7]0.98OS57.1 [50.2-64]53[46-60]0.62Table 2:main causes of deathCauses of deathATG group n,(%)Non ATG group n,(%)Relapse13 (46.3)36 (46)GvHD3 (10.7)9 (11.5)Infection2 (7)12 (15.5)Organ toxicity5 (18)11 (14)Secondary neoplasia1 (3.6)1 (1.5)Rejection02 (2.5)Unknown4 (14.4)7 (9) DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation (Allo-SCT) for De Novo Ph+ Acute Myeloid Leukemia: A Study from the French Society of Bone Marrow Transplantation and Cell Therapies

Introduction: De novo Ph+ acute myeloid leukemia (AML) has recently been described as a distinct AML subtype with a specific genome signature compared to chronic myeloid leukemia (CML). Although Allo-SCT is often proposed as the curative option, the outcome of Ph+ AML treated with Allo-SCT remains unknown in the literature.Methods: Between 2000 and 2012, 19 patients with Ph+ AML who received Allo-SCT were identified in France and compared to 21 patients with Ph+ biphenotypic acute leukemia (BAL) and 52 patients with myeloid blast crisis CML (MBC-CML). Clinical data were prospectively collected though ProMISe (Project Manager Internet Server), an internet-based system shared by all centers of The French Society of Bone Marrow Transplantation and Cell Therapies. The study was approved by local ethical committee.Results: For AML, BAL and MBC-CML patients, the median age per group was respectively 46 (18-67), 36 (18-52) and 36 (18-63) years. Median follow-up was 24 months. Additional cytogenetic abnormality was not different between the 3 groups. The MBC-CML group had a lower rate of induction therapy before Allo-SCT compared to the 2 other groups and a lower rate of remission status before transplant (p<0.0001). However tyrosine-kinase inhibitor (TKI) exposure during induction was similar in each arm. A myelo-ablative conditioning regimen was used in 72% of cases without difference in each group. However the Ph+ BAL group received significantly more TBI-cyclophosphamide conditioning regimen compared to the Ph+ AML and MBC-CML groups (p<0.03). No difference was observed between the 3 groups concerning graft source or the use of antithymocyte globulin (ATG). Acute graft-versus-host disease (aGVHD) with a grade≥2 was observed respectively in 37%, 19% and 32% of the Ph+ AML, BAL and MBC-CML groups. Chronic GVHD incidence was 42%, 24% and 27% in the 3 groups. Relapse I ncidence was 28%, 29% and 49% in the 3 groups. Two-year overall survival probability for Ph+ AML, BAL and MBC-CML was 65.5% (45.4-79.7), 58.3% (32.7-71.4), 38.3% (95% CI: 26.2-50.3), respectively (p=0.016, log-rank test, Figure 1). Two-year cumulative incidence of non-relapse mortality (NRM) was 17.7% (0.07-0.4) for Ph+ AML, 25.96 % (0.12-0.49) for Ph+ BAL and 33.2% (0.21-0.49) for the MBC-CML group. In univariate analysis, remission status and type of disease (Ph+ AML) were predictive factors for a better survival rate. The onset of GVHD was also predictive of a better overall survival (HR 0.43 [0.23-0.78], p=0.006).Conclusion: Limited data are available on de novo Ph+ AML. This study showed a promising 65% two-years overall survival in Ph+ AML subtype in comparison with others Ph+ acute leukemia. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Peripheral Blood Stem Cells Vs Bone Marrow: Stem Cell Source Comparison for Patients Acute Myeloid Leukemia and Myelodysplastic Syndrome Receiving an Allogeneic Stem Cell Transplantation from a 10/10 Matched Donor. Study from the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Introduction: Peripheral blood stem cells (PBSC) are increasingly used for unrelated donor (UD) hematopoietic stem cell transplantation (HSCT). A recent randomized prospective trial did not detect significant survival differences between PBSC and bone marrow (BM) transplantation from a UD. The use of PBSC reduced the risk of graft failure, whereas BM reduced the risk of chronic graft versus host disease (GVHD) (Anasetti & al, NEJM 2012). However, HLA matching was based on HLA-A, HLA-B, HLA-C &HLA-DRB1 (8/8 but also 7/8), some of the patients (pts) received a reduced intensity conditioning regimen (22%) and diseases consisted of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but also other hematological malignancies. We thus conducted this study to compare mobilized PBSC with BM for matched 10/10 UD HSCT after standard conditioning regimen (MAC) in pts with AML and MDS only.Patients and methods: We included all consecutive pts in France who received a first HSCT for AML or MDS with PBSC or BM from a matched 10/10 UD after a MAC (fractionated total body irradiation (TBI)-Cyclophosphamide(Cy), n=165 or Endoxan-Cy, n=203) between 2000 and 2013. Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). HLA typing data were collected from the SFHI (French Society of Histocompatibility and Immunogenetic) and the ABM (French Biomedical Agency). This study is in accordance with Helsinki declaration for clinical research.Results: We included368 adults pts (221 [60%] received BM; 147 [40%] received PBSC). Median follow-up was of 16.5 months [0-156]. The BM and PBSC groups were well balanced with respect to age, diagnosis, disease risk, use of antithymocyte globulins (ATG) (67 [30%] BM and 52 [35%] PBSC recipients,) and cytomegalovirus (CMV) recipient and donor status. PBSC recipients were more likely to be male and received less TBI-based regimen. GVHD prophylaxis mainly combined cyclosporine A (CSA) and methotrexate (MTX) (82%).The median number of nucleated cell dose infused was higher in the PBSC group compared with the BM group: CD34+ cells, 6.96 x10⁶/kg [1.2-37.8] vs 2,78 x10⁶/kg [0.6-89] p<0.01) and total nucleated cells, 9.8 x10⁸/kg [1.3-663] vs 2.3 x10⁸/kg [0.3-305.3] p<0.01).Two hundred and seven (90%) pts engrafted after BM and 144 (99.3%) after PBSC HSCT (p=0.1). Among pts who received PBSC as compared with those who received BM, the median time to neutrophils engraftment (> 0.5 x 109 /L) was 6 days shorter and 8 days shorter to platelets engraftment (>20x109 /L) (p<0.01).The cumulative incidence (CI) for severe acute GVHD III-IV was 21.1% and 16.3% in the PBSC and the BM group, respectively (p=0.18).CI of chronic GVHD was higher after PBSC (47.1% vs 34.3% for BM, p=0.05). By multivariate analysis, the absence of ATG in the conditioning regimen (HR 0.4 95%CI [0.22-0.72] p<0.01) and PBSC as stem cells source (HR 0.6 95%CI [0.34-0.97] p=0.04) were associated with an increased chronic GVHD.At 2-years, the CI of non relapse related mortality (NRM), relapse as well as disease free survival (DFS) and overall survival (OS) were similar between the 2 groups (Table 1).In multivariate analysis, better OS was associated with complete remission (CR) disease status (HR 0.5 95%CI [0.32-0.69] p<0.01) and pts’s age<38.1 years (HR 0.67 95%CI [0.48-0.93] p=0.02) at time of HSCT, and the use of CSA-MTX as GVHD prophylaxis (HR 0.6 95%CI [0.41-0.95] p=0.03).Conclusion: OS, NRM and relapse rates are similar with PBSC and BM after HLA 10/10 matched UD for AML or MDS using MAC, but engraftment is better with PBSC and the CI of chronic GVHD is lower with BM. Better results are obtained for pts <38 years old with a disease in CR at time of HSCT using CSA-MTX as GVHD prophylaxis. The absence of ATG with PBSC was associated with chronic GVHD. This study thus favors the use of ATG in the setting of matched 10/10 PBSC. However, the role of ATG in the context of BM after HLA 10/10 matched UD MAC HSCT remains unclear and warrants further investigation.Table 1:2-year CI of NRM*, relapse, DFS** and OS***ParametersBM % (95% CI)PBSC % (95%CI)p valueNRM23 (20-26)18 (15-21)0.8Relapse30 (27-33)28 (25-31)0.83DFS47.1 (44-51)54.4 (50-58)0.2OS54 .4 (50.8-57.9)60.2 (55.7-64.6)0.31*NRM: non-relapse mortality**DFS: disease free survival***OS: overall survival DisclosuresNo relevant conflicts of interest to declare.

Effect of Immune Modulation for Peripheral T-Cell Lymphoma in Response to Relapse after Allogeneic Hematopoietic Stem Cell Transplant: A Study of 63 Patients By the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC).

Introduction:Peripheral T-cell lymphomas (PTCL) are heterogeneous diseases, lightly sensitive to chemotherapy, with an adverse outcome and a 5-year survival rate of about 30%. Allogeneic hematopoietic stem cell transplant (allo-SCT) can lead to durable remission even for patients (pts) who show poor response to chemotherapy. Several observations argue for a Graft Versus Lymphoma (GVL) effect in PTCL. However, allo-SCT is not consensually recommended, at least in first line therapy. The aim of the current study is to highlight GVL effect in PTCL. To do so, we evaluated the benefits of immune modulation on disease control (donor lymphocyte infusions (DLI) and immunosuppressive therapy tapering) with analysis of outcome in pts who relapsed after allo-SCT.Patient selection and methods:Between 1988 and 2012, 373 pts received an allo-SCT for treatment of PTCL. 80 pts in relapse after allo-SCT were identified in 27 SFGM-TC(French Society of Bone Marrow Transplantation and Cell Therapies) transplant centers. Exhaustive data were collected for 63 pts. Median age at transplant was 45 years; 67% were male. The main histopathologic subtypes were T-nos (20, 32%), primary cutaneous TCL (13, 21%) and anaplastic large TCL (11, 17%). Others were angioimmunoblastic TCL (8), T/NK lymphomas (5), HTLV1 lymphomas (5) and EIATL (1). At transplant, 38% were in complete remission (CR), 43% in partial remission (PR) and 19% had progressive disease. Median number of previous lines of treatment was 2 and 25% of the pts had previously received an autologous SCT. Conditioning regimen was myeloablative for 23 pts and non-myeloablative for 40. At relapse, pts were treated with either non-immunologic-based strategy (chemotherapy, radiotherapy) or immune modulation (DLI and/or discontinuation of immunosuppressive therapy), or both (Figure 1). We analyzed their outcomes according to the treatment they received at relapse.Results:Relapse occurred at a median time of 204 days after transplant (interquartile range: 49-190 days); seventeen pts had a localized cutaneous relapse (7 Mycosis fungoides, 2 angioimmunoblastic TCL, 3 T-nos, 3 anaplastic TCL and 2 NK/TCL). Among the 14 pts (22%) who received DLI (DLI alone: 5, DLI + radiation and/or chemotherapy: 9), 9 obtained a response (7CR, 2 PR) and 2 had a stable disease (SD) status (overall response rate: 78%). Six of these 14 pts remained alive at last follow up. Median overall survival (OS) of these 14 pts was 23.6 months. Among the 49 pts who did not receive DLI, immunosuppressive therapy was tapered or stopped for 23. Sustained CR after tapering immunosuppressive drugs was observed in2 pts along with extensive chronic graft versus host disease (cGVHD). In the non-DLI group, 30 out of 49 pts received a radio/chemotherapy treatment with a response rate of 50% and a 1-year survival rate of 25% after relapse. Among the 13/49 pts who experienced a response in this group, six developed a cGVHD after relapse. Median OS of these 49 pts was 3.6 months. Median follow up was 40 months for the whole population.Conclusion:DLI alone or in association with other therapies, when possible, seems to be an efficient salvage option. This study suggests the benefit of DLI in cases of post transplant relapse for PTCL and supports the existence of a GVL effect in these diseases. These findings could potentially lead to the set up of a proactive immune modulation strategy after transplant for pts with high-risk disease. However, the short time frame from transplant to relapse currently observed, might limit the feasibility of this therapeutic option. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Contribution of IPSS-R Cytogenetics to Predict Outcome after Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes: A Study from the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)

The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation (allo-SCT) is critically determined by cytogenetic abnormalities. In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 patients with MDS transplanted from HLA-identical siblings or HLA allele-matched unrelated donors. According to the C-IPSS-R 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk and 10 (3%) in the very poor risk group. In multivariate analysis, the poor and very poor-risk categories correlated with shorter overall survival (HR = 1.59, P = 0.009 and HR = 3.18, P = 0.002, respectively) and higher relapse rates (HR = 1.82, P = 0.004 and HR = 2.44, P = 0.060, respectively), after a median follow-up of 4 years. Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group with dismal prognosis. These findings urge the investigation of new post-transplant therapeutic approaches for patients with very poor C-IPSS-R karyotypes, including maintenance therapy. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation Following Reduced-Intensity Conditioning Regimen for Elderly Patients (60 years and older) with Hematological Malignancies Using Unrelated Donors: A Retrospective Study on Behalf of the French Society for Stem Cell Transplantation and Cell Therapies (SFGM-TC)

▪Background: Reduced intensity conditioning (RIC) regimen has allowed the extension of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to a previously unreached population of older patients for whom hematologic malignancies aremore common. The use of unrelated donors (UD) in patients aged of 60 years or more has drastically increased in the past few years. To date, there are only limited data on the feasibility and outcomes of UD allo-HSCT in elderly patients (60 years or more). The purpose of the current study is to describe outcomes in a large cohort of patients aged 60 years or older who received a RIC UD allo-HSCT in recent years.Patients and methods: Between 2008 and 2012, this retrospective multicenter study included 539 consecutive patients aged of 60 years or more (142 aged 65 or more and 9 aged 70 or more) who received a first allo-HSCT for hematological malignancies (351 with myeloid disorders and 188 with lymphoid malignancies) from an UD (HLA matched at HLA-A, -B, -C, -DQ and –DRB1, 10 out of 10 alleles in 95% of cases) after a RIC regimen (Peripheral blood stem cells in 92% of cases) in France. In 85% of the patients, conditioning regimen was fludarabine-based and Graft versus Host Disease (GvHD) prophylaxis consisted of cyclosporine (CSA) plus MMF in 47% of cases and CSA plus methotrexate in 20%. To address the role of age by itself in our population, 2 groups of patients were defined: patients with age at allo-HSCT less than 65 years old (“UD<65 group”, n=397) and patients who were aged 65 years or more (“UD ≥ 65 group”, n=142). Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all centers of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC). This study was approved by the scientific committee of the SFGM-TC and is in accordance with the declaration of Helsinki for clinical research.Results: Patient characteristics were similar between the 2 groups (UD<65 group and UD ≥ 65 group) for time between diagnosis and allo-HSCT, gender, disease (myeloid versus lymphoid), disease status (complete remission at allo-HSCT versus others), source of stem cells, number of infused total nucleated and CD34 cells, donor age, donor gender, patient/donor sex mismatch, HLA matching, patient/donor CMV (cytomegalovirus) status, the use of antithymocyte globulins (ATG) or TBI-based regimen (2 gray only), and GvHD prophylaxis. Patients in the UD ≥ 65 group received more CD3 cells (p=0.02). The median follow-up was 36 months (range, 0.3-73.5) for UD<65 group and 32 months (range, 0.03-72) for UD≥65 group. During evolution, the cumulative incidence (CI) of grade II–IV acute GvHD was 36% in UD<65 group and 31% in UD≥65 group (p= 0.684) while the CI of chronic GvHD at 2 years was 42% and 35%, respectively (p= 0.334). CI of treatment related mortality (TRM), disease free survival (DFS) and overall survival (OS) were not different between the 2 groups (Table 1). Multivariate analysis for TRM, DFS and OS show that age by itself has no influence.Conclusion: These data suggest equivalence of outcome between UD<65 group and UD≥65 group after RIC UD allo-HCT in this large cohort of elderly patients ( above 60 years old ) with hematological malignancies. Age by itself thus appears not to be a limitation in this particular population of elderly patients.Table 1:2-year cumulative incidence of TRM, DFS and OSCharacteristicsTRMDFSOSAll patients29%42%49%Patients aged less than 65 years (UD<65 group)28%41%49%Patients aged 65 years or more (UD≥65 group)33%47%51%p value0.3500.4170.809 DisclosuresBeguin:Genzyme / Sanofi: Research Funding. Michallet:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hospira: Consultancy, Honoraria.

Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction: BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes.

Bone marrow (BM) cell therapy for ischemic heart disease (IHD) has shown mixed results. Before the full potency of BM cell therapy can be realized, it is essential to understand the BM niche after acute myocardial infarction (AMI). To study the BM composition in patients with IHD and severe left ventricular (LV) dysfunction. BM from 280 patients with IHD and LV dysfunction were analyzed for cell subsets by flow cytometry and colony assays. BM CD34(+) cell percentage was decreased 7 days after AMI (mean of 1.9% versus 2.3%-2.7% in other cohorts; P<0.05). BM-derived endothelial colonies were significantly decreased (P<0.05). Increased BM CD11b(+) cells associated with worse LV ejection fraction (LVEF) after AMI (P<0.05). Increased BM CD34(+) percentage associated with greater improvement in LVEF (+9.9% versus +2.3%; P=0.03, for patients with AMI and +6.6% versus -0.02%; P=0.021 for patients with chronic IHD). In addition, decreased BM CD34(+) percentage in patients with chronic IHD correlated with decrement in LVEF (-2.9% versus +0.7%; P=0.0355). In this study, we show a heterogeneous mixture of BM cell subsets, decreased endothelial colony capacity, a CD34+ cell nadir 7 days after AMI, a negative correlation between CD11b percentage and postinfarct LVEF, and positive correlation of CD34 percentage with change in LVEF after cell therapy. These results serve as a possible basis for the small clinical improvement seen in autologous BM cell therapy trials and support selection of potent cell subsets and reversal of comorbid BM impairment. http://www.clinicaltrials.gov. Unique identifiers: NCT00684021, NCT00684060, and NCT00824005.