Prolonged Transportation Time Of Haemopoietic Progenitor Cells Does Not Impact Upon Engraftment Or Overall Survival Following Allogeneic Voluntary Unrelated Donor Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 694-694
Author(s):  
Cheryl J Hutchins ◽  
Jason P Butler ◽  
Angela McLean ◽  
Judith Y Cummings ◽  
Geoff R Hill ◽  
...  

Abstract Introduction The transportation of haemopoietic progenitor cells (HPC) from collection centre to transplant centre is a critical, but often overlooked process during allogeneic transplantation using voluntary unrelated donors (VUD). The policies of international donor registries support the rapid retrieval and infusion of HPC. However transplant centres are often challenged by transit times in excess of 24h when retrieving HPC from intercontinental collection centres. This single institutional retrospective study aimed to investigate if a prolonged transit time between collection and transplant centre impacted upon the rate of engraftment and overall survival of recipients of HPC collected from VUDs. Methodology A retrospective analysis of outcomes following an initial allogeneic transplant performed at our institution between 1987 and 2013 was conducted using institutional databases. The time to neutrophil and platelet engraftment and overall survival was compared between recipients of VUD transplants with HPC retrieved from collection centres located overseas (transit time of > 24h) (n = 241; BM n = 50, PBPC n = 191), recipients of unrelated donor transplants with HPC retrieved from collection centres within Australia (transit time of <8h) (n = 334; BM n = 112, PBPC n = 222) and recipients of related HPC collected at the transplant centre (n = 807; BM n = 320, PBSC n = 487). All HPC retrieved from local and intercontinental VUD collection centres were transported in rigid coolers containing refrigerated gel packs prior to 2003 or isothermal cooling inserts post 2003. The temperature was monitored and maintained by the courier at between 2 and 8oC. Results There was no significant difference in the days to neutrophil and platelet recovery (Table 1) between recipients of a VUD allogeneic transplant with HPC retrieved from a local collection centre compared with those recipients whose HPC was retrieved from an international collection centre. Retrieval and infusion of HPC from local collection centres is generally completed within 8h from collection whereas the interval from collection to infusion may vary between 24 to 90h when HPC are retrieved from intercontinental collection centres. Furthermore there was no significant difference in overall survival (Figure 1) of recipients of related donor allogeneic transplants performed without transportation of HPC and recipients of VUD allogeneic transplants whose HPC were retrieved from either a local collection centre or an intercontinental collection centre (Figure 1). Conclusion Our study demonstrated no adverse effect on neutrophil and platelet recovery, or overall survival resulting from retrieval of HPC (BM and PBPC) from collection centres with transit times in excess of 24h and with some international retrievals requiring up to 90h transit times. A previous study had reported higher mortality rates and delayed platelet engraftment following HLA matched unrelated donor BM transplants facilitated by the National Marrow Donor Program with an interval of greater than 24h between collection and infusion (Lazarus et. al, Biol Blood Marrow Transplant 15: 589-596, 2009). At our centre HPC (BM and PBPC) are retrieved by trained couriers that monitor and maintain the temperature between 2 and 8oC. This is in contrast to NMDP recommendations that BM is transported at ambient temperature. Our data suggest that all HPC should be refrigerated to between 2 and 8oC and the temperature monitored during transportation. In addition, the courier should be trained to re-establish the optimal temperature for transportation if the temperature deviates from the recommended range. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1159-1159
Author(s):  
Haowen Xiao ◽  
Xiaoyu Lai ◽  
Gongqiang Wu ◽  
Yi Luo ◽  
Jimin Shi ◽  
...  

Abstract Abstract 1159 Poster Board I-181 Background In allogeneic SCT, genetic factors such as donor and recipient gene polymorphisms of pro- and anti-inflammatory cytokines have been associated with the incidence and severity of GVHD. However, the influence of such donor and recipient gene polymorphisms on other outcomes, such as early infection after SCT, has seldom been described. TNFαa, TNF receptorII (TNFRII), IL-10 and TGF gene contain multiple single nucleotide polymorphisms (SNPs) in the promoter and codon region. We thus studied the association of this panel of candidate gene polymorphisms with the incidence of the first episodes of early bacterial infections within 100 days after allo-HSCT. Methods A total of 138 unrelated donor/recipient pairs, who had undergone HLA-matched allo-HSCT from January 2001 to March 2009 at the First Affiliated Hospital of Zhejiang University School of Medicine, were tested for TNFαa(TNFαa-857 C>T, TNFαa-863 C>A, TNFαa-1031 T>C), TNFRII (codon196 T>G), IL-10 (IL10-1082 A>G, IL10-819 T>C, IL10-592 A>C), TGF (TGF-509 T>C, TGF+869 C>T) polymorphism allele frequencies and genotype. SNPs were analysed by Multiplex SnaPshot. We considered the first episodes of early bacterial infections within 100 days after allo-HSCT have developed when sepsis, pneumonia, or septic shock was diagnosed according to previously published criteria. Results (1) 133 patients achieved complete donor chimerism in the peripheral blood and 5 patients had graft failure. All patients achieved an absolute neutrophil count (ANC) greater than 0.5×109/L at day 13 (7∼22) and platelet recovery at day 15 (7∼64). The cumulative incidence of at least one bacterial infection was 47.8% (pneumonia and intestinal infection are the most popular) within 100 days after allo-HSCT. There is no significant difference in the time to neutrophil recovery in patients who experienced early bacterial infections with those who did not (13.6 vs 12.8,P=0.115). (2) The TNFαa-857 C/C genotype and TNFRII 196 T/T genotype of the donor were significantly associated with a higher risk of early bacterial infection ( for TNFαa-857 C/C genotype: 53.3% vs 29.0%, P=0.024 ; TNFRII 196 T/T genotype: 53.5% vs 33.3%, P=0.038); (3) The TGF-509 T/T genotype of the donor was significantly associated with a higher risk of early bacterial infection (62.5% vs 41.8, P=0.038); (4) Transplantation from donors with IL10-819 C/C genotype or IL10-592 C/C genotype were significantly associated with a higher risk of early bacterial infection (for IL10-819 C/C genotype: 71.4.1% vs 45.3%, P=0.034; IL10-592 C/C genotype: 70.0.1% vs 45.8%, P=0.055); (5) The genotypes of TNFαa-863, TNFαa-1031, IL10-1082 and TGF+869 were not found to be associated with the risk of early bacterial infection. Conclusions Recent studies have shown that the generation potential of IL-10 is influenced by the polymorphism of the IL-10 gene. The IL10-819*C allele and IL10-592 *C allele are associated with higher secretion of IL-10 than IL10-819*T allele and IL10-592*A allele. In our data, a higher risk of early bacterial infection with IL10-819 C/C and IL10-592 C/C genotype was postulated to be associated with a higher IL-10 production, which suppressed reactive T-cell response. These results, which is the first report of TNFαa, TNFRII, IL-10and TGF polymorphic features of Chinese population with the risk of early bacterial infection after HLA-matched unrelated allo-HSCT, suggest an interaction of the donor TNFαa-857C/C, TNFRII 196 T/T, IL10-819 C/C, IL10-592 C/C and TGF-509 T/T genotypes on risk of early infection. These results are helpful for predict allo-HSCT outcome, identify more suitable donors and clarify therapy on an individual patient basis. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 227-227 ◽  
Author(s):  
Bronwen E. Shaw ◽  
Katharina Fleischhauer ◽  
Mari Malkki ◽  
Theodore Gooley ◽  
Elisabetta Zino ◽  
...  

Abstract Abstract 227 It is well established that the use of a donor matched for 9–10/10 alleles at HLA-A,-B,-C,-DRB1,-DQB1 significantly improves overall survival (OS) after unrelated donor (UD) haematopoietic stem cell transplantation (HSCT). Whilst the matching status for HLA-DPB1 alleles has been shown to influence transplant complications (relapse and graft-versus-host disease (GVHD), its impact on survival has not been well defined. The current unmet need in clinical practice is an approach to stratify selection criteria when a clinician is confronted with the choice between several 10/10 or 9/10 matched unrelated donors. There is now considerable interest in exploring different types of matching criteria to define permissive HLA-DPB1 mismatches which may be associated with an improved outcome. We have previously shown that HLA-DPB1 permissiveness can be functionally defined by the characterization of shared T cell epitopes (TCE) recognized by alloreactive T cells. In this model, allelic HLA mismatches are classified as permissive if they do not involve TCE disparities, and as non-permissive if they do. Using this concept, we developed two overlapping algorithms of permissivity for allelic HLA-DPB1 mismatches, on the basis of 3 (TCE3) or 4 (TCE4) groups of DPB1 alleles encoding immunogenic TCE. Data from relatively small prospective studies has shown a worse outcome to be associated with non-permissive DPB1 TCE disparities. Here, we present outcomes in 9123 UD-HSCT pairs, collected through the International Histocompatibility Working Group (IHWG). The cohort was comprised of 5809 10/10 matched transplant pairs and 3314 9/10 matched pairs. Within the 10/10 and 9/10 matched pairs three groups of patients were identified: 1. Zero DPB1 mismatches (i.e. allele matched), 2. Permissive DPB1 mismatch, 3. Non-permissive DPB1 mismatch. The model was adjusted for disease severity, source of stem cells, conditioning regimen, use of T-cell depletion, patient/donor gender and patient age. In line with DPB1 allele frequencies in worldwide populations, the number of transplants scored as permissive was higher for TCE3 (4398/7270 [60.4%]) than for TCE4 (2577/7270 [35.4%]). Using the DPB1 permissive mismatch transplants as the reference group (either 10/10 or 9/10 matched), we showed that DPB1 allelic matches resulted in similar survivals to DPB1 permissive mismatches, both in the 10/10 (HR 0.96, p=0.498 for TCE3 and HR 0.99, p=0.85 for TCE4) and the 9/10 setting (HR 0.97, p=0.70 for TCE3 and HR 0.99, p=0.96 for TCE4). In contrast, survival was significantly worse in the presence of a non-permissive TCE3 or TCE4 mismatch, both in the 10/10 (HR 1.15, p=0.0005 for TCE3 and HR 1.13, p=0.0035 for TCE4) and in the 9/10 matched setting (HR 1.13, p=0.0140 for TCE3 and HR 1.11, p=0.0448 for TCE4). The survival detriment appeared to be due to a significantly increased non-relapse mortality (TCE3: 10/10 HR 1.27, p<0.001 and 9/10 HR 1.21, p=0.0001; TCE4: 10/10 HR 1.24, p<0.001 and 9/10 HR 1.13, p=0.0514), as well as an increase in grades II-IV acute GVHD (TCE3: 10/10 HR 1.17, p<0.001 and 9/10 HR 1.29, p<0.001; TCE4: 10/10 HR 1.12, p=0.0035 and 9/10 HR 1.19, p<0.0001). There was no significant difference in disease relapse between permissive and non-permissive mismatched pairs. Finally, using the 10/10 DPB1 permissive mismatched group as a reference, we found survival to be similar for 10/10 DPB1 non-permissive (HR 1.15) and 9/10 DPB1 permissive (HR 1.20) or DPB1 allele matched (HR 1.17) transplants. In conclusion, our results suggest that extending donor selection to include HLA-DPB1 both allelic and functional TCE matching may result in better prediction of survival for patients. These findings provide an attractive new algorithm to stratify donor choice when several well-matched UD are identified. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3018-3018
Author(s):  
Iwona Mitrus ◽  
Andrzej Smagur ◽  
Sebastian Giebel ◽  
Joanna Gliwinska ◽  
Magdalena Prokop ◽  
...  

Abstract Abstract 3018 Background: Cryopreservation of autologous peripheral blood progenitor cells (PBPCs) in 10% DMSO is a routine in most transplantation centers. During ASH 2011 Meeting, we presented the results of in vitro research, concerning the optimization of DMSO concentrations for recovery and clonogeneic potential of PBPCs after thawing. We concluded, that reduction of DMSO concentration from 10% to 7.5% may have favorable impact for cell clonogeneicity. Accordingly, we implemented new cryoprotective mixture (7.5% instead of 10% DMSO) into clinical practice. The purpose of this study was to clinically evaluate the changed protocol. Patients and Methods: In our department, between Jan 2012-Aug 2012, 56 patients were transplanted with autologous PBPCs cryopreserved in 7.5% DMSO solution (median of age: 57 years, range: 21–66). We compared the data concerning hematopoietic engraftment and the frequency of side effects with historical control – 52 subsequent patients treated with transplantation of PBPSc cells cryopreserved in 10% DMSO (median of age: 57 years, range: 21–66) in a preceding period. Both study groups did not differ significantly with regard to the diagnosis (mostly lymphoproliferative disorders) or disease status at transplantation. As well, the number of transplanted CD34+ cells was comparable: median 6.5′106/kg (range 1.5–24.7) for 7.5% DMSO and 7.5′106/kg (2.1–24.6) for 10% DMSO group, p=0.68. All received G-CSF (filgrastim) starting on day +7 after transplantation. Results: The volume of infused DMSO was significantly lower in patients who obtained PBPBc cryopreserved in 7.5% DMSO (median 22.5 ml, range 7.5–45) than 10% DMSO (median: 30 ml, range, 10–160); p=0.02. The time to leukocyte recovery >1′109/L was faster for 7.5% DMSO (median: 11 days, range: 9–12) than in 10% DMSO (median 11 days, range: 10–13), p=0.03. Similarly, reconstitution of neutrophils >0.5′109/L was faster for 7.5% DMSO group: median 11 days (range 9–13 days) vs. 11 days (range 10–13 days), respectively; p = 0.04. We didn't observe significant difference with regard to platelet recovery >50′109/L (median 12 days, range: 0–21 days for 7.5% DMSO vs. median 12.5, range: 0–19 days for 10% DMSO). Hospital stay since HSCT was shorter in case of 7.5% group (median: 14 days, range: 11–21) than 10% group (median: 15 days, range: 13–25); p=0.04. Number of RBC and platelets transfusions as well as transfusion-related complications did not differ between the groups. Adverse events after transplantation were mild and transient, usually grade 1 nausea, and occurred in 20 (38%) patients in 10% DMSO group compared to 24 (43%) in 7.5% DMSO group (p=0.7). Conclusions: The analysis of newly implemented cryopreservation protocol suggest that reduction of the DMSO concentration from 10% to 7.5% is associated with faster leukocyte and neutrophil recovery as well as shorter hospital stay. These findings require verification in a prospective, randomized trial. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
1993 ◽  
Vol 81 (8) ◽  
pp. 2031-2035 ◽  
Author(s):  
NJ Chao ◽  
JR Schriber ◽  
K Grimes ◽  
GD Long ◽  
RS Negrin ◽  
...  

Abstract Hematopoietic growth factors have been used to accelerate engraftment after bone marrow transplantation and to “mobilize” peripheral blood progenitor cells (PBPC). We report on the data in 85 consecutive patients with Hodgkin's disease who were treated in a single institution using different methods to obtain PB progenitor cells. Use of granulocyte colony-stimulating factor for mobilization resulted in a significantly accelerated time to recovery of granulocytes (10 days v 12 days, P < .01) when compared with “nonmobilized” PBPC recipients. Similarly, use of mobilized PBPC resulted in a significantly accelerated time to platelet engraftment (13 days v 30 days, P < .001) when compared with “nonmobilized” recipients. Moreover, there was a statistically significant difference in total costs in favor of the group receiving “mobilized” PBPC.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 531-531
Author(s):  
Mary Eapen ◽  
Jennifer LeRademacher ◽  
H. Joachim Deeg ◽  
Joseph H. Antin ◽  
Richard Champlin ◽  
...  

Abstract Abstract 531 Unrelated donor HSCT has been considered a therapy of last choice in SAA, because of poor overall survival reported prior to 1998 (32% @ 5-years). This is due in large measure to low resolution donor-recipient HLA typing and the selection of patients. Survival after unrelated donor BM HSCT for SAA has improved in recent years with survival rates of approximately 75% @ 5-years when the donor and recipient are matched at HLA-A, -B, -C and –DRB1. Furthermore, improvements in conditioning regimen may also have reduced the rate of graft rejection. In recent years PBPC instead of BM are increasingly used and PBPC grafts now account for 25% of unrelated donor HSCT for SAA. An earlier report from the CIBMTR and the EBMT identified higher chronic graft-versus-host disease (GVHD) incidence and mortality after transplantation of PBPC from HLA-matched siblings compared to BM in patients with SAA aged ≤20 years. GVHD rates are higher after unrelated adult donor HSCT regardless of graft type, but the effects of PBPC on survival in patients with SAA are not known. Two hundred and forty nine patients transplanted in 2000–2007 received either BM (n=186) or PBPC (n=63) from unrelated adult donors matched at HLA-A, -B, -C, -DRB1. Median follow up was 3 years. Compared with recipients of BM, PBPC recipients were older (median age: 19 vs. 35 years), transplanted in 2006–2007 (37% vs. 46%), more likely to be male (47% vs. 65%), receive non-TBI containing transplant conditioning (fludarabine + cyclophosphamide or busulfan or melphalan ± anti-thymocyte globulin; 34% vs. 55%) and tacrolimus-containing GVHD prophylaxis (29% vs. 57%). Among patients who received TBI-containing regimens, approximately 90% of BM and PB recipients received TBI 200 cGy. There were no differences in patient performance score at HSCT, immunosuppressive treatment prior to HSCT and interval from diagnosis to HSCT (median time to HSCT was 13 months in BM recipients and 11 months, in PBPC recipients). As shown after HLA-matched sibling transplantation, the cumulative incidence of neutrophil recovery (30.5 × 109/L at day-28) and platelet recovery (≥20 × 109/L) was similar in recipients of BM (92% and 83%, respectively) and PBPC (95% and 90%, respectively). The day-100 probability of grades 2–4 acute GVHD was higher after PBPC than after BM (51% vs. 33%, p=0.01). The 3-year probability of chronic GVHD was higher after PBPC than after BM, in patients older than 20 years at HCT (60% vs. 41%, p=0.001) but not in younger patients (23% vs. 26%, p=NS). In multivariate analysis, the risk of mortality was higher after PBPC than after BM (HR 1.79, p=0.02). Other factors that predicted mortality included poor performance score (HR 1.95, p=0.009) and non-TBI transplant conditioning regimens (HR 1.96, p=0.006). Although patient age (>20 vs. ≤20 years) was significantly associated with chronic GVHD there was no significant effect of age on mortality (HR 1.21, p=0.47). The 3-year probability of overall survival adjusted for performance score and transplant conditioning regimen was 76% for BM and 60% for PBPC recipients (p=0.02). These data suggest that: 1) outcomes after URD HSCT for SAA are now similar to outcomes observed in MRD HSCT, 2) BM is the preferred graft source when considering unrelated donor HCT in patients with SAA and 3) the data also support low dose TBI in the preparative regimen for transplant conditioning. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2029-2029
Author(s):  
Hui-Sheng Ai ◽  
Xiao-Jun Huang ◽  
Zhen-Hua Qiao ◽  
Jian-Min Wang ◽  
Ying-Min Liang ◽  
...  

Abstract Abstract 2029 Reduced-intensity conditioning (RIC) transplantation has been widely used in the treatment of hematological diseases. However, the comparison of long-term outcomes of RIC with HLA-matched, HLA–mismatched and unrelated donor is still lacking. Here, we reported the results of hematological patients treated at the China RIC Cooperative from the HLA-matched, HLA–mismatched and unrelated donor following to RIC. 514 patients with hematological diseases from the China RIC Cooperative Group were enrolled in this study, including 370 in HLA-matched group, 96 in HLA-mismatched group and 48 in unrelated group (table 1). The RIC conditioning regimen was based on fludarabine in combination with antilymphocyte globulin or busulfan or others. The graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A, mycophenolate mofetil and methotrexat. Results showed that 505 patients achieved stable donor chimerism. The incidence of II-IV aGVHD in the HLA-mismatched group was 42.7%, significantly higher than that in the HLA-matched group (21.4%) and the unrelated group (20.8%). The 100-day transplantation-related mortality was 30.2%, 14.5% and 4.2% in the three groups, respectively. The median follow-up time was 57 months (range,7 to 141 months). The overall relapse incidence was 14.8%, including 15.7% in the HLA-matched group, 14.6% in the HLA-mismatched group and 8.3% in the unrelated group. There was no significant difference in relapse incidences in the patients with AL-CR1 and CML-CP (16.4% and 11.2%), as well between the HLA-matched group (16.9% and 16.7%) and the unrelated group (11.1% and 8.8%). For the patients with advanced leukemia, a significantly lower relapse rate was found in the HLA-mismatched group in comparison with that in the HLA-matched group (18% vs 36.2%, p<0.05, Fig. 1).The Kaplan-Meier estimated DFS and OS at 6 years for all of the 514 patients were 58.6% and 61.9% respectively, and those at 11 years were 57.8% and 61.7% respectively. The DFS and OS at 6 years in the HLA-mismatched group was 35.4% and 38.5% respectively, lower than those at 11 years in the HLA-matched group (62.7% and 67.0%, p<0.01) and those at 6 years in the unrelated group (64.6% and 66.7%, p<0.01, Figure 2 A, B). The 11-year DFS for the patients with AL-CR1, CML-CP and MDS/SAA was 68.7%, 68.5% and 73.6% respectively in the HLA-matched group. The 6-year DFS for the patients with AL-CR1, CML-CP and MDS/SAA was 55.6%, 70.7% and 62% respectively in the unrelated group, and 37.5%, 62.5% and28.6% respectively in the HLA-mismatched group. Figure 2 C,D,E£© However, the 6-year DFS in the patients with advanced leukemia was 32.0% in the HLA-matched related group, similar to that in the HLA-mismatched group (31.9%, p£¾0.05, Fig. Figure 2 F). These results indicate that RIC transplantation had similar outcome in the HLA-matched group and unrelated group but better than that from the HLA-mismatched group in haematology diseases. However, for the advanced leukemia patients, the HLA-mismatched transplantation had much lower leukemia relapse rate than in the HLA-matched group. Fig 1: The relapse rate of the patients with advanced leukemia in the HLA-mismatched group and the HLA-matched group. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4007-4007
Author(s):  
Katrine Nielsen ◽  
Lea Bjerre ◽  
Hanne Oestergaard Larsen ◽  
Peter Hokland ◽  
Anne Stidsholt Roug

Abstract Abstract 4007 Background: An increasing body of evidence in different organ systems suggests that the presence of the cytosolic enzyme Aldehyde Dehydrogenase (ALDH) correlates to stemcellness. Thus, in mobilized peripheral blood stem cells (PBSCs), the side scatter low ALDH bright (SSCloALDHbr) population seems to be highly enriched for HSC as determined e.g. by Fallon et al1. However, these interesting preliminary findings need confirmation. Problem formulation: The generally accepted indirect relationship between CD34 content on the one hand, and successful hematopoietic regeneration after transplant on the other, is at least to a certain extent marred by the observation that, despite receiving sufficient weight-correlated amounts of CD34 positive HSC, some patients experience prolonged time to regeneration. Hypothesis: We hypothesized that the number of CD34+SSCloALDHbr is predictive of time to short and long-term regeneration following autologous bone marrow transplantation compared to the number of CD34+ cells alone. Results: PBSCs from 30 patients with refractory or relapsed diffuse large cell B-lymphoma referred for autologous stem cell transplantation after having failed at least three cytoreductive regimens were analyzed for ALDH expression. Laboratory results were registered on day 14 and day 100 post transplantation. Time to absolute neutrophil count (ANC) above 0,5 × 106/mL on two consecutive days was registered for each of the 30 patients. While a trend was noted for number of reinfused viable CD34+ cells (106/kg) to be correlated to ANC > 0,5 × 106/mL r=0.33, P = 0.07), only the CD34+SSCloALDHbr population correlated significantly to time to ANC > 0,5 × 106/mL (r=0.41, P =0.024). Moreover, while a positive correlation was observed between both of the analyzed subpopulations and CFU-GM proliferation, this correlation was strongest for the number of reinfused CD34+SSCloALDHbr/kg (r= 0.84, P <0.001). While neither of the analyzed subpopulations could be correlated to time to short term platelet recovery (defined as platelets > 20 × 106/mL on two consecutive days) an interesting finding emerged, when we considered day 100 platelet recoveries. Here, 11 patients were grouped as poor mobilizers (PM) having not attained a platelet count of 100 × 106/mL at day 100, and 16 patients were grouped as good mobilizers (GM) while in three cases no data were available. While mere CD34 enumeration was once more not informative, we observed a trend towards low numbers of CD34+SSCloALDHbrcells in the grafts in PM (p=0.06). With regard to long-term erythroid engraftment (defined as Hgb<100 g/L at day 100) 6 were PM (21 GM and data missing in 3) a significantly lower fraction of reinfused CD34+SSCloALDHbrwere administered to PM compared to GM (p=0.01). Once more, no significant difference in number of infused viable CD34+ cells between the groups was observed. Conclusion: In the autologous transplant setting the addition of SSCloALDHbrto standard CD34 enumeration seems to constitute a valuable marker for the identification of both time to ANC > 0,5 × 106/mL and inferior day +100 hematopoietic regeneration. While the assay does entail extra lab efforts, this layout is probably amply repaid by the possibility to institute pre-emptive therapy in PM patients. Moreover, application of the assay at the onset of leukapheresis sessions could provide a window of opportunity to administer alternative mobilization regimens, i.e. containing Plerixafor. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4088-4088
Author(s):  
Colombe Saillard ◽  
Roberto Crocchiolo ◽  
Sabine Furst ◽  
Jean El-Cheikh ◽  
Luca Castagna ◽  
...  

Abstract Abstract 4088 Background: Chronic graft-versus-host disease (cGvHD) after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies is associated with lower relapse rate, due to graft-versus-tumor effect. We know that the extensive form is associated with higher transplant-related mortality after myeloablative conditioning regimen, mainly due to infectious complications as a consequence of immunosuppressive treatment. Beside the “classical” Seattle classification (limited or extensive form), a recent classification (from National Institute of Health, NIH) distinguishes three levels of severity: limited, moderate and severe. We compare here both classifications for patients receiving reduced-intensity conditioning (RIC) transplant and looked for any association of cGvHD severity with transplant outcome. Patients and Methods: We evaluated data on all adult patients with hematological lymphoid or myeloid malignancies who received HSCT from related or unrelated donor, using peripheral blood stem cells, after RIC regimens (with fludarabine-busulfan-ATG) between 1998 and 2010 at the Institut Paoli-Calmettes (Marseille, France). Data on main pre- and post-transplant variables were collected; cGvHD was classified according to its presentation and severity (with both Seattle and NIH classifications) and was correlated with overall survival (OS), non relapse mortality (NRM), and relapse. cGvHD was considered as time-dependent variable, and was included in uni- and multivariate models, after adjusting for age, disease risk, HLA compatibility, graft source and comorbidity score. Relapse or death before cGvHD was considered as a competing event. Results: 283 patients were evaluated, 121 have developed cGvHD (27 limited forms and 94 extensive forms), 162 have not, for an incidence rate of 10% and 33% of limited and extensive forms respectively. Median follow up was 607 days, patients had a median age of 50 years, transplanted for acute leukemia (55), lymphoma (78), multiple myeloma (49), myelodysplastic syndrome (24), CLL (12), CML (16) or others malignancies (19). Peripheral stem cells were mostly used (294 versus 20 bone marrow graft). We had 241 related donors and 77 unrelated donors. The median day of cGvHD occurrence was 132, we found 52 de novo forms, 40 quiescent and 26 progressive forms. After reclassification with NIH criteria, we obtained 28 mild, 52 moderate and 41 severe forms. 22 of 27 limited forms were classified as mild, the extensive forms were divided into 49 moderate and 39 severe forms. In multivariate analysis, mild and moderate forms were associated with better OS compared with other groups. Severe cGvHD was associated with significant increase in NRM. Among the other variables, only age was statistically significative in OS and NRM models. Although the incidence of relapse was lower in patients with cGvHD compared with those without, no significant difference was seen between the 3 groups of patients presenting it. Conclusion: Following a fludarabine-busulfan-ATG RIC, it seems that mild to moderate cGVHD forms are associated with better OS than patients without or with severe cGVHD. This is related to lower NRM than patients with severe cGVHD and at least a comparable antitumoral effect with respect to patients without cGVHD. This invites developing strategies limiting severity but not abrogating the effect of cGVHD. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1891-1891
Author(s):  
Yutaka Hattori ◽  
Yurika Ikeda ◽  
Yuya Suzuki ◽  
Daiju Ichikawa ◽  
Maiko Matsushita

Abstract Backgrounds and purpose Recently, newly developed drugs such as thalidomide, lenalidomide and bortezomib have significantly improved survival of the patients with multiple myeloma (MM). However, certain group of the patients who have characteristic high-risk cytogenetic changes such as deletion of TP53 tumor suppressor gene revealed significantly shorter survival. In patients with deletion of TP53 gene, the somatic point mutation in the residual TP53 gene has been reported to be rare. Thus, the exact role of alteration of TP53 gene in high-risk myeloma remains unclear. Polymorphism of TP53 gene at codon 72 in exon 4, CGC to CCC transition, leads to arginine (Arg) to proline (Pro) amino-acid substitution. Biological analyses showed that the Arg variant more efficiently induces expression of P21 and apoptosis via Ser-6 and 20 phosphorylation of p53 protein. In contrast the Pro variant is less resistant to MDM-2-mediated degradation and more potently induced cell-cycle arrest and DNA damage repair. Recently, clinical significance of this polymorphism has been extensively studied in solid tumors as well as hematological malignancies including non-Hodgkin lymphoma and leukemia. However, consistent association of the polymorphism with cancer risk has not been elucidated. The purpose of this study is to examine codon 72 polymorphism in patients with refractory multiple myeloma (MM) treated with thalidomide, and to elucidate its association with myeloma risk and outcome of thalidomide-therapy. Patients & methods A total of 37 Japanese patients with refractory or relapsed MM who were treated with thalidomide monotherapy were included in this study. Three cases showed deletion of TP53 gene by fluorescence in situ hybridization (FISH) analyses. The codon 72 polymorphism was evaluated in the rest of 34 patients. Genomic DNA was isolated from bone marrow mononuclear cells. The genomic TP53 gene was amplified by polymerase chain reaction, and the amplified DNAs were directly sequenced. Results Direct DNA sequence showed that the Pro/Pro homozygote was observed in six patients (18%), Pro/Arg heterozygote in 12 (35%) and Arg/Arg homozygote in 16 (47%). There was no significant difference in the frequency of the polymorphism between the 34 Japanese MM patients and the healthy Japanese individuals (P=0.44). Thus, association of codon 72 polymorphism with myeloma risk has failed to be elucidated. The response rate to thalidomide therapy was 33% in the patients with Pro/Pro, 27% in Pro/Arg and 44% in Arg/Arg (P=0.49), respectively. Other clinical backgrounds including age, sex, Durie-Salomon stage, ISS stage, serum creatinine, albumin, b2M, calcium, hemoglobin levels and M-protein type were not correlated with TP53 codon 72 polymorphism, either. Progression free survival (PFS), overall survival (OS) and post-relapse survival were shown in Figure 1. The patients with Pro allele tended to show shorter PFS; 5 weeks for the patients with Pro/Pro versus 32 weeks for those with Pro/Arg plus Arg/Arg (P=0.07) (Figure 1). Overall survival (OS) of the patients with Pro/Pro, Pro/Arg and Arg/Arg allele was 18 weeks, 49 weeks and 133 weeks, respectively (P=0.027). Especially, the patients with Pro/Pro allele revealed significantly shorter OS compared with those with Pro/Arg plus Arg/Arg (18 weeks versus 100 weeks, P=0.023) (Figure 1). Significant difference of OS in patients with Pro/Pro+Pro/Arg vs Arg/Arg (P= 0.032) suggested the dominant effect of Pro allele for poorer prognosis. Post-relapse survival of the patients with Pro/Pro, Pro/Arg and Arg/Arg allele was 11, 42 and 64 weeks, respectively (P=0.054). Post-relapse survival for Pro/Pro versus Pro/Arg plus Arg/Arg were 11 weeks versus 64 weeks (P=0.029). Conclusion These results indicated that codon 72 polymorphism did not correlated with myeloma risk, but significantly associated with therapeutic outcome. Namely, the patients with Pro allele revealed earlier relapse and shorter post-relapse survival, resulted in shorter OS in thalidomide therapy. Further evaluation is needed to clarify whether the codon 72 polymorphism will be a new prognostic marker for the treatment with novel drugs. Disclosures: No relevant conflicts of interest to declare.


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