Peripheral Progenitor Cell Graft in the Rat: A Technique of Graft Processing

The aim of this study was to establish a procedure for blood progenitor cell graft processing in rats.  As a first step the mobilization protocol was optimized. The second step was dedicated to define the optimal  source for subsequent graft manufacturing: either peripheral blood or spleen. The third step was  designed to establish a protocol for purification of stem cells. The best mobilization results in terms of white blood cell count, granulocyte colony forming units (CFUG)  and CD90 positive progenitor cells were obtained after pre-treatment of the donors for 5 days with  recombinant human granulocyte colony stimulating factor (100 μg/kg) in combination with murine stem  cell factor (33 μg/kg). Splenectomy prior to mobilization increased the yield of stem cells from peripheral blood. The numbers of  CD90-positive progenitor cells recovered from the spleen of one rat after stem cell mobilization were sufficient  to generate one stem cell graft. Grafts containing 1 x 106 progenitor cells – and thus sufficient for transplantation - were obtained after Tcell  depletion and positive selection of CD90 positive cells. The grafts were characterized and showed a  purity exceeding 70%, a T-cell depletion of 3.6 log10 and a 3-fold increase in CFU-G compared to the yield  post mobilization.

Association of Human Development Index with rates and outcomes of hematopoietic stem cell transplantation for patients with acute leukemia

Abstract Human Development Index (HDI) is used by the United Nations Organization to measure socioeconomic achievements of countries. We evaluated the association of HDI with rates and outcomes of hematopoietic stem cell transplantation (HSCT) for patients with acute leukemia. For the analysis of HSCT rates, all adults with acute leukemia (n = 16 403) treated in 30 European countries, between 2001 and 2005, were included. Association of HDI with the outcome was analyzed for 2015 patients with acute myeloid leukemia treated with myeloablative allotransplantation. Countries were classified according to HDI quintiles. Highly significant correlation was found for HDI and the total number of HSCT per population (R = 0.78; P < .001), as well as separately for sibling HSCT (R = 0.84; P < .001), unrelated HSCT (R = 0.66; P < .001), and autologous HSCT (R = 0.43; P = .02). The probabilities of leukemia-free survival for 5 consecutive groups of countries with increasing HDI were: 56%, 59%, 63%, 58%, and 68% (P = .01). In a multivariate analysis, transplantations performed in countries belonging to the upper HDI category were associated with higher leukemia-free survival compared with the remaining ones (HR = 1.36, P = .008), which resulted mainly from reduced risk of relapse (HR = 0.72, P = .04). We conclude that, in Europe, the HDI is associated with both rates and results of HSCT for acute leukemia

Outcomes of haploidentical stem cell transplantation for chronic lymphocytic leukemia: a retrospective study on behalf of the chronic malignancies working party of the EBMT

Allogeneic hematopoietic stem cell transplantation (HCT) may result in long-term disease control in high-risk chronic lymphocytic leukemia (CLL). Recently, haploidentical HCT is gaining interest because of better outcomes with post-transplantation cyclophosphamide (PTCY). We analyzed patients with CLL who received an allogeneic HCT with a haploidentical donor and whose data were available in the EBMT registry. In total 117 patients (74% males) were included; 38% received PTCY as GVHD prophylaxis. For the whole study cohort OS at 2 and 5 yrs was 48 and 38%, respectively. PFS at 2 and 5 yrs was 38 and 31%, respectively. Cumulative incidence (CI) of NRM in the whole group at 2 and 5 years were 40 and 44%, respectively. CI of relapse at 2 and 5 yrs were 22 and 26%, respectively. All outcomes were not statistically different in patients who received PTCY compared to other types of GVHD prophylaxis. In conclusion, results of haploidentical HCT in CLL seem almost identical to those with HLA-matched donors. Thereby, haploidentical HCT is an appropriate alternative in high risk CLL patients with a transplant indication but no available HLA-matched donor. Despite the use of PTCY, the CI of relapse seems not higher than observed after HLA-matched HCT

an ALWP-EBMT study

Background Allogeneic stem cell transplantation is the only curative option for patients with acute myeloid leukemia (AML) experiencing relapse. Either matched sibling donor (MSD) or unrelated donor (UD) is indicated. Methods We analyzed 1554 adults with AML transplanted from MSD (n = 961) or UD (n = 593, HLA-matched 10/10, n = 481; 9/10, n = 112). Compared to MSD, UD recipients were older (49 vs 52 years, p = 0.001), transplanted more recently (2009 vs 2006, p = 0.001), and with a longer interval to transplant (10 vs 9 months, p = 0.001). Conditioning regimen was more frequently myeloablative for patients transplanted with a MSD (61 vs 46 %, p = 0.001). Median follow-up was 28 (range 3–157) months. Results Cumulative incidence (CI) of neutrophil engraftment (p = 0.07), grades II–IV acute GVHD (p = 0.11), chronic GVHD (p = 0.9), and non-relapse mortality (NRM, p = 0.24) was not different according to the type of donor. At 2 years, CI of relapse (relapse incidence (RI)) was 57 vs 49 % (p = 0.001). Leukemia-free survival (LFS) at 2 years was 21 vs 26 % (p = 0.001), and overall survival (OS) was 26 vs 33 % (p = 0.004) for MSD vs UD, respectively. Chronic GVHD as time-dependent variable was associated with lower RI (HR 0.78, p = 0.05), higher NRM (HR 1.71, p = 0.001), and higher OS (HR 0.69, p = 0.001). According to HLA match, RI was 57 vs 50 vs 45 %, (p = 0.001) NRM was 23 vs 23 vs 29 % (p = 0.26), and LFS at 2 years was 21 vs 27 vs 25 % (p = 0.003) for MSD, 10/10, and 9/10 UD, respectively. In multivariate analysis adjusted for differences between the two groups, UD was associated with lower RI (HR 0.76, p = 0.001) and higher LFS (HR 0.83, p = 0.001) compared to MSD. Interval between diagnosis and transplant was the other factor associated with better outcomes (RI (HR 0.62, p < 0.001) and LFS (HR 0.67, p < 0.001)). Conclusions Transplantation using UD was associated with better LFS and lower RI compared to MSD for high-risk patients with AML transplanted in first relapse

Inferior outcome of allogeneic stem cell transplantation for secondary acute myeloid leukemia in first complete remission as compared to de novo acute myeloid leukemia

Following chemotherapy, secondary acute myeloid leukemia (sAML), occurring after antecedent hematologic diseases, previous chemotherapy or radiation, has an inferior prognosis compared with de novo AML. To define the outcome of sAML in the context of allogeneic stem cell transplantation (alloSCT), a retrospective, registry-based comparison was performed, including 11,439 patients with de novo and 1325 with sAML. Among transplants in first complete remission (CR1) (n = 8,600), the 3-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 28.5% and 16.4% for de novo, and 35% and 23.4% for sAML. Three-year overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 1.33 [95% CI = 1.21-1.48]; p <10(-5)), LFS (HR = 1.32 [95% CI = 1.19-1.45]; p <10(-5)) and GRFS (HR = 1.2 [95% CI = 1.1-1.31]; p <10(-4)) and higher NRM (HR = 1.37 [95% CI = 1.17-1.59]; p <10(-4)) and RI (HR = 1.27 [95% CI = 1.12-1.44]; p <10(-3)). Results of the Cox model were confirmed in a matched-pair analysis. In contrast, results did not differ between de novo and sAML after alloSCT in induction failure or relapse. Hence, this analysis identified sAML as an independent risk factor for outcome after alloSCT in CR1.Peer reviewe

The impact of concomitant cytogenetic abnormalities on acute myeloid leukemia with monosomy 7 or deletion 7q after HLA-matched allogeneic stem cell transplantation

Monosomy 7 or deletion 7q (-7/7q-) is the most frequent adverse cytogenetic features reported in acute myeloid leukemia (AML), and is a common indication for allogeneic stem cell transplantation (SCT). Nevertheless, -7/7q- occurs frequently with other high-risk cytogenetic abnormalities such as complex karyotype (CK), monosomal karyotype (MK), monosomy 5 or deletion 5q (-5/5q-), 17p abnormalities (abn(17p)) or inversion of chromosome 3 (inv(3)), the presence of which may influence the outcomes after SCT. A total of 1109 patients were allocated to this study. Two-year probability of leukemia-free survival (LFS) and overall survival (OS) were 30% and 36%, respectively. Two-year probability of non-relapse mortality (NRM) was 20%. We defined five different cytogenetic subgroups: the "-7/7q- +/- CK group- designated group1," the "MK group-designated group 2," the "-5/5q- group- designated group 3," the "abn(17p) group- designated group 4" and the "inv(3) group- designated group 5." The 2-year probability of LFS in first remission was 48% for group 1, 36.4% for group 2, 28.4% for group 3, 19.1% for group 4 and 17.3% for group 5, respectively (P <.001). Multivariate analysis confirmed those significant differences across groups. Note, SCT in -7/7q- AML provides durable responses in one third of the patients. The presence of -7/7q- with or without CK in the absence of MK, abn(17p) or inv (3) is associated with a better survival after SCT. On the contrary, addition of MK, -5/5q-, abn(17p) or inv(3) identifies a sub-group of patients with poor prognosis even after SCT.Peer reviewe

Metallicity and Far-Infrared Luminosity of High Redshift Quasars

We present the results of an exploratory study of broad line region (BLR) metallicity in 34 2.2 < z < 4.6 quasars with far-infrared (FIR) luminosities (L_FIR) from 10^13.4 to 10^12.1 L_\odot . Quasar samples sorted by L_FIR might represent an evolutionary sequence if the star formation rates (SFRs) in quasar hosts generally diminish across quasar lifetimes. We use rest-frame ultraviolet spectra from the Sloan Digital Sky Survey to construct three composite spectra sorted by L_FIR, corresponding to average SFRs of 4980, 2130 and 340 M_\odot yr^-1 after correcting for a nominal quasar FIR contribution. The measured N V {\lambda} 1240/C IV {\lambda} 1550 and Si IV {\lambda} 1397+O IV] {\lambda} 1402/C IV {\lambda} 1550 emission line ratios indicate super-solar BLR metallicities in all three composites, with no evidence for a trend with the star formation rate. The formal derived metallicities, Z ~ 5-9 Z_\odot , are similar to those derived for the BLRs of other quasars at similar redshifts and luminosities. These results suggest that the ongoing star formation in the host is not responsible for the metal enrichment of the BLR gas. Instead, the BLR gas must have been enriched before the visible quasar phase. These results for high quasar metallicities, regardless of L_FIR, are consistent with evolution scenarios wherein visibly bright quasars appear after the main episode(s) of star formation and metal enrichment in the host galaxies. Finally, young quasars, those more closely associated with a recent merger or a blowout of gas and dust, may exhibit tracers of these events, such as redder continuum slopes and higher incidence of narrow absorption lines. With the caveat of small sample sizes, we find no relation between L_FIR and the reddening or the incidence of absorption lines.Comment: 10 pages, 3 figures. Accepted to MNRAS, May 201