Peripheral Blood Stem Cells Group Research Articles

Mobilized Peripheral Blood Stem Cells Compared with Bone Marrow as the Stem Cell Source for Unrelated Donor Allogeneic Transplantation with Reduced-Intensity Conditioning in Patients with Acute Myeloid Leukemia in Complete Remission: An Analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Reduced-intensity conditioning allogeneic stem cell transplant (RIC-alloSCT) is being increasingly used for patients with acute myelogenous leukemia (AML) with comorbidities. Few published data are currently available regarding for the use of peripheral blood stem cells (PBSCs) compared to bone marrow (BM) in the RIC-alloSCT using unrelated donors (URDs). This retrospective report compared the outcomes of PBSC versus BM RIC-alloSCT. Between 2000 and 2007, 602 patients with AML in complete remission (CR) underwent RIC-alloSCT from URDs with PBSC (508) or BM (94) grafts. Recipient's age was higher in the PBSC versus BM groups 57 (range, 17-77 years) and 51 (range, 17-76 years), respectively (P < .0001). Leukemia features and disease status at RIC-alloSCT were also comparable between the PBSC versus BM groups. Engraftment was achieved in 97% and 96% with BM versus peripheral blood (PB), respectively. Acute graft-versus-host disease (aGVHD) grade >II was significantly higher in the PBSC group: 27% versus 12% in the BM group (P < .002). Similarly, chronic graft-versus-host disease (cGVHD; at 2 years) was somewhat higher in the PBSC group with 43% ± 3% versus 35% ± 6% in the BM group, respectively (P = .04). The 2-year probabilities of leukemia-free survival (LFS) were 46% ± 3% for the PBSC group in comparison to 43% ± 6% for the BM transplant group (P = NS), whereas relapse incidence was significantly higher in the BM versus the PB transplant group: 46% ± 6% versus 32% ± 3%, respectively (P = .014). Non-relapse mortality (NRM) was significantly higher for the PBSC versus the BM group: 28% ± 2% versus 13% ± 4%, respectively (P = .004). In multivariate analysis, after adjustment for differences between both groups, the PBSC group was associated with a higher incidence of aGVHD (grade II-IV; hazard ratio [HR] = 2.33; P = .06), higher NRM (HR = 2.3; P = .015), and a decreased relapse incidence (HR, 0.61; P = .02) with no statistical difference of LFS between the 2 groups (P = .88). In conclusion, our results indicate significantly higher incidence of aGVHD and NRM and a lower incidence of relapse but not statistically different LFS comparing unrelated PBSC to BM grafts after RIC-alloSCT.

Nonpharmacologic Treatment of Chronic Graft-versus-Host Disease in Children and Adolescents

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many children with life-threatening diseases. One of the most significant long-term complications of transplantation is chronic graft-versus-host disease (cGVHD). Although the rates of cGVHD after HSCT are lower in the pediatric population than in adults, cGVHD remains a significant cause of morbidity and mortality. Medicines used to prevent and treat cGVHD remain unsatisfactory, with protracted use of immune suppression necessary and high rates of first-line treatment failure. Efforts to improve salvage treatment are urgently required. Nonpharmacologic strategies attempt to modulate the cellular inflammation response and possibly allow reduction or cessation of immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been shown invitro to mediate a wide variety of immune responses. MSC have been used in the prophylaxis of acute GVHD (aGVHD) and for the treatment of established steroid refractory aGVHD and, more recently, in the management of cGVHD. Extracorporeal photochemotherapy (ECP) has shown promising efficacy in graft-versus-host disease, and may allow a significant reduction in the use of systemic steroids and other immunosuppressants, reducing long-term morbidity and mortality. The accumulated experience shows ECP to be well tolerated, with no clinically significant side effects.

Cryopreservation of Peripheral Blood Stem Cells From Matched Related and Unrelated Donors Is Associated with Delayed Neutrophil and Platelet Engraftment but Does Not Influence Relapse-Free Survival

Abstract 2998Cryopreservation of peripheral blood stem cells (PBSC) for allogeneic transplantation (allo-SCT) has potential advantages including ensuring an adequate stem cell dose is available prior to commencing transplant conditioning and allowing more flexible transplant scheduling. Concerns that cryopreservation may impair engraftment have, however, limited its use. In addition, no published series have examined cryopreservation of matched unrelated donor (MUD) PBSC. In this study, we assessed engraftment and survival following allo-SCT using cryopreserved PBSC. Seventy-six allo-SCT using cryopreserved PBSC were assessed: 57 from HLA matched family donors and 19 from MUD where HLA allelic match was 10/10 (n=14) or 9/10 (n=5). Transplants were performed between 2004 and 2010. Indications for allo-SCT were myeloid malignancy (n=50) or lymphoid malignancy (n=26). Disease was early phase in 51 (67.1%) and late phase in 25 (32.9%) patients. Conditioning was myeloablative (MAC) in 27 and reduced intensity (RIC) in 49 patients, 49 patients received in vivo T cell depletion with alemtuzumab or anti-thymocyte globulin. Median follow-up (FU) of survivors was 41 months. Comparison was made against a broadly matched control group comprising 79 allo-SCT using fresh PBSC.Cumulative incidence of neutrophil engraftment to >0.5 × 109/L at day 14 was (95% confidence interval (CI)) 73.3% (61.–82) vs 92.3% (83.4–96.5) for cryopreserved vs fresh PBSC respectively. Neutrophil engraftment was significantly delayed (P=0.00031, Log-rank test) in the cryopreserved group but neutrophil engraftment at day 30 was identical at 99% in both groups. Platelet (plt) engraftment to >50 × 109/L at day 14 was 27.6% (18.8–38.1) vs 58.9% (47.1–69) for cryopreserved vs fresh PBSC respectively, P<0.0001. Cumulative incidence of plt engraftment at day 30 was 72.3% (60.3–81.2) vs 96.2% (87.4–98.9) for cyropreserved and fresh PBSC respectively. In multivariate analysis delayed neutrophil engraftment was associated with cryopreservation (hazard ratio (HR)=1.59, 95% CI 1.2–2.13, P=0.0014), MAC (HR=1.67, 95%CI 1.22–2.3, P=0.0015) and lymphoid malignancy (HR=1.49, 95% CI 1.11–2, P=0.0077). Delayed plt engraftment was associated with cryopreservation (HR=2.17, 95% CI 1.49–3.13, P<0.0001) and related donor transplant (HR=1.46, 95% CI 1.05–2, P=0.025). Eight patients, 6 in the cryopreserved and 2 in the fresh PBSC group required CD34 selected PBSC ‘top-up' for primary engraftment failure, 5 of whom (4 cryopreserved, 1 fresh) were alive at last follow-up. One patient in the fresh and none in the cryopreserved PBSC group experienced late secondary graft failure. Relapse-free survival at 2 years was 40.7% (30.4–54.4) vs 50.2% (39.6–63.6) P=0.42 for cryopreserved vs fresh PBSC respectively. There were no significant differences in relapse incidence, transplant-related mortality, incidence of grades II-IV acute graft-vs-host disease or extensive chronic GvHD between cryopreserved and fresh PBSC.Whilst cryopreservation of PBSC for allo-SCT in both matched related and MUD allo-SCT is associated with significantly delayed neutrophil and platelet engraftment, only delayed platelet engraftment is likely to be of clinical significance. Survival was comparable to allo-SCT using fresh PBSC. In lieu of evidence from prospective trials, PBSC cryopreservation should be considered as an option in selected patients for whom its benefits outweigh the risks of delayed engraftment. Disclosures:Craddock:Celgene: Honoraria, Research Funding.

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

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

The Use of Bone Marrow Graft for Hematopoietic Stem Cell Transplantation From Matched Unrelated Donors After Reduced Intensity Conditioning Regimen Improves Survival : Analysis of the Societe Française De Greffe De Moelle Et De Therapie Cellulaire.

Abstract 873The use of peripheral blood stem cells (PBSC) for hematopoietic stem cell transplantation (HSCT) is associated with a higher risk of chronic graft versus host disease (GvHD) but its impact on survival is not clear since it may favor a greater graft versus leukemia (GvL) effect. However, in the context of HSCT from unrelated donors (UD), the balance between GvH and GvL may differ from the context of sibling donors and thus the use of PBSC may be deleterious. In this retrospective study, we analyzed 103 patients from the french registry who received a graft from an UD after a reduced intensity conditioning regimen (RIC) to evaluate the role of various parameters including the source of stem cells on the outcome. Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The median age was 46 years (18-67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. The conditioning regimen was Fluda/TBI 2Gys for 26 patients, Bu/Fluda/ATG for 24 patients, Fluda/Melph for 16 patients and others for 37 patients. Overall, anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The source of stem cells was PBSC for 65 patients and bone marrow (BM) for 38 patients. The median follow up of the cohort is 61,3 months (1,2-113,7). The results showed that 95% of patients engrafted. Five patients did not engraft (4 in the BM group and 1 in the PBSC group). Acute GvHD grade II to IV and grade III/IV occurred in 47% and 19% of patients, respectively. The risk of developing chronic GvHD was 49% at 2 years. Overall survival (OS) was 36% at five years. The median disease free survival (DFS) was 55 months among the 36 patients alive. We performed univariate and multivariate analysis of factors susceptible to impact on GvHD and survival. The multivariate analysis included the impact of HLA mismatch, disease status, diagnosis, source of stem cells, patient's and donor's ages. This multivariate analysis performed on the global population shows a trend towards an improved OS with the use of BM instead of PBSC. However, when focusing the multivariate analysis on the 71 patients transplanted with a 10/10 match donor, the most potent factor influencing the outcome is the use of BM which is associated with an improved OS (p=0.03) and DFS (p=0.02), less acute GvHD grade II-IV (p=0.05), or grade III/IV (p=0.05) and less chronic GvHD (p=0.05). These results suggest that the use of BM as the source of stem cells should be reconsidered in the context of matched UD after RIC transplantation. Disclosures:No relevant conflicts of interest to declare.

A retrospective comparison of allogeneic peripheral blood stem cell versus bone marrow transplantation

Disease evolution depends in part on the source of transplanted cells. Therefore, we compared outcomes after allogeneic bone marrow (BM) and peripheral blood stem cell (PBSC) transplantation in patients who underwent transplant at Hospital das Clinicas of the Federal University of Minas Gerais, Brazil. We studied 364 patients who received allogeneic BM (n = 142) or PBSC transplantation (n = 222) between July 1995 and May 2005. The median age of the patients was 31 years (range, 3.1-58 years). Chronic myeloid leukemia was the predominant diagnosis (41.2%). A conditioning regimen with cyclosphosphamide and busulfan was used in 79.4% (n = 289) and graft-versus-host disease (GVHD) prophylaxis was cyclosporine/methotrexate in 95.9% (n = 349) of cases. The patients in the PBSC group had faster neutrophil (P < .001) and platelet engraftment (P = .03) but increased rates of acute GVHD (P < .001) vs. those in the BM group. There was no significant difference between the groups in chronic GVHD, transplant-related mortality, relapse and survival rates. Although allogeneic PBSC transplant results in a faster hematopoietic engraftment, there was an increase in acute GVHD. There was no clear benefit in relapse rate and no evidence that transplantation with PBSC benefits patient survival in our institution.

Unrelated Allogeneic Stem Cell Transplantation with Myeloablative Conditioning in Adults with Acute Lymphoblastic Leukemia in Remission: Peripheral Blood or Bone Marrow?.

With the objective to compare outcomes of peripheral blood stem cells (PBSC) and bone marrow (BM) in patients with ALL in remission, we have studied 388 adults with ALL given an unrelated BMT and 337 PBSCT reported to EBMT from 1998 to 2004. The donors were HLA identical (HLA-A and -B low resolution and HLA-DRB1 allelic typing). Median age was 27 years for BM (range 16–63, male 60%) and 30 years for PBSC (range 16–63, male 62%), respectively. Fifty nine and 68% of patients were transplanted in first complete remission (CR1) in the BM and PBSC groups. Female donor to male recipient constellation was 18% in the BM and 15% in the PBSC group. Total Body Irradiation (TBI)-based preparative regimens were given in 85% and 88% of patients in the BM and PBSC group respectively. GvHD-prophylaxis consisted of cyclosporine A (CsA) (6% and 4%), CsA and methotrexate (77% and 58%) or in vivo T-cell depletion (17% and 38% in BM and PBSC group). With the median follow-up of 19 and 13 months, the incidence of GvHD grade II–IV was 37% in the BM group and 39% in the PBSC group (p=0.39). Probabilities of LFS, NRM and relapse were calculated using the Kaplan-Meier estimate. LFS was 45+/−3% vs 36+/−3% (p=0.03) nonrelapse related mortality (NRM) was 30+/−3% and 34+/−4 (p=0.39) while incidence of relapse (RI) was 24+/−4% and 30+/−5% (p=0.13), in the BM and PBSC groups respectively. Three years LFS for the patients transplanted in CR1 was 48% (BM) and 42% (PBSC, p=0.48). In a multivariate analysis adjusting for differences in patients with CR1 in both groups showed not statistically difference for RI, NRM and LFS. However, 3-years LFS for patients transplanted in CR2 was significantly higher in the BM (n=159) compared to the PBSC group (n=106) (40% and 27%, p<0.04). The RI was significantly lower in BM compared to PBSC (33% vs 54%, p<0.01) without there being a detectable difference in NRM at 3 years (40% vs 40%, p= 0.59). This finding led us to look in more details CR2 group of ALL patients. There was no statistically difference between patients receiving BM or PBSC regarding the incidence of Ph'+ or t(4;11) (20% vs 37% in BM and PBSC group), B-lineage (80% vs 76%, respectively) and T-lineage ALL (20% vs 24%, respectively), but patients were older in the PBSC group at the time of transplant (24y vs 27y, p= 0.02) and they received more in vivo T-cell depleted transplants by using antithymocyte globulin (p=0.02). The interval from diagnosis to transplant was longer in BM group (977d vs 687 d in BM and PBSC group, p=0.02). Three years LFS with an interval from diagnosis to Tx > 30 months was not different in BM and PBSC group (48% vs 42%, p=0.65). However, there was a significant difference in LFS in BM group (32%) in comparison to PBSC group (17%) if an interval from diagnosis to Tx <30 mo (p=0.001). The incidence of chronic GvHD in adult ALL in CR2 was 53% and 40% in PBSC and BM, respectively (p=0.09). After statistical adjustments for differences between the two groups, the interval from diagnosis to Tx <30 mo was a risk factor for LFS. In addition, TBI-based conditioning and the interval from diagnosis to Tx <30 mo were risk factors for RI. In conclusion, UD-SCT with either BM or PBSC as a graft source is an effective treatment for adult ALL patients in CR1 and CR2 when the interval between diagnosis and transplant is superior to 30 months. In patients transplanted in CR2 with an interval from diagnosis to Tx<30 months outcomes are worse independent of the cell source used.

Potential Increase in Graft Failure Risk after Reduced Intensity Conditioning Stem Cell Transplant (RIT) Using Umbilical Cord Blood for Children with Primary Immunodeficiency.

Allogeneic stem cell transplantation is curative for patients with primary immunodeficiency. A unique reduced intensity conditioning regimen has been developed to maximize cure rate and minimize transplant-related toxicity. Between 2000 and 2007, we performed 16 RIT in patients with hyper-IgM syndrome (n=2), severe combined immune deficiency (SCID) (n=10), immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) (n=2), Wiskott-Aldrich syndrome (n=1), and X-linked lymphoproliferative disease (n=1). There were 12 males and 4 females, with a median age at the time of RIT of 8.0 months (range 1.1 months to 8.9 years). Donor sources included peripheral blood stem cells (PBSCs) from matched related donors (n=7) or unrelated donors (n=2), and cord blood units (CBUs) (n=7). The median cell dose was 8.55 × 108 total nucleated cells (TNC)/kg and 6.7 × 106 CD34+cells/kg for the PBSC group, and 1.99 × 108 TNC/kg and 0.71 × 106 CD34+cells/kg for the CBU group. The conditioning regimen consisted of Fludarabine (Flu), days -10 through -5, intravenous Busulfan (Bu), days -5 and -4, and Anti-thymocyte globulin (ATG), days -4 through -1. GVHD prophylaxis included tacrolimus/prednisone (n=1), cyclosporine A (CSA) alone (n=2), and CSA/mycophenolate mofetil (n=13). All patients who received PBSCs from related and unrelated donors engrafted (9/9), whereas only 4/7 (57%) patients who received CBUs engrafted. The 3 patients who experienced primary graft failure had the following diagnoses; IPEX, T−B−NK+ SCID and T−B+NK+ SCID. Their cord blood doses were 0.78, 1.19 and 1.99 × 108 TNC/kg, and 0.11, 0.69, and 0.55 × 106 CD34+cells/kg, respectively. For the 13 patients who engrafted, median time to absolute neutrophil count (ANC) >1000 was 19 days (range 4 to 53) and median time to platelets >50K was 23 days (range 14 to 90). The ANC never dropped <500 for 8/13 (62%) patients, and platelets never dropped <20K for 9/13 (69%) patients who engrafted. VNTR analysis of donor cell contribution showed that full donor chimerism was achieved in 8/16 patients (50%; 6 received PBSCs and 2 received CBUs), and, partial donor chimerism was achieved in 5/16 patients (31%; 3 received PBSCs and 2 received CBUs). Toxicities within 100 days post-RIT included bacteremia (n=8), candidemia (n=1), and viral infection (n=6). All infections were effectively treated and patients fully recovered. No episodes of seizure or veno-occlusive disease were experienced. No mucositis or severe nausea/vomiting was reported. No grade III/IV acute graft-versus-host disease (GVHD) or chronic GVHD was seen. Three patients died within 100 days post-RIT from causes related to primary or secondary graft failure. The overall survival was 81.0% at 2 year post-RIT (95% CI 89.5–71.5). All deceased patients received CBUs as the donor source. One of these patients were considered high-risk with pre-RIT Lansky score =30%. If this patient was excluded from analysis, the 100 day RIT related mortality was 13.3%. This retrospective analysis revealed that RIT with Flu/Bu/ATG conditioning is well tolerated in children with primary immunodeficiency. The use of CBUs, however, appeared to increase the risk of graft failure. A larger study of the use of RIT in primary immunodeficiency could further examine this hypothesis.

Transplantation of Peripheral Blood Stem Cells from Unrelated Donors Is Not Associated with Inferior Survival Compared to Bone Marrow Transplantation in Children with Hematologic Malignancies - A Registry Analysis from the German/Austrian Pediatric Registry for Stem Cell Transplantation (PRST).

The optimum stem cell source for allogeneic hematopoietic stem cell transplantation (HSCT) remains highly controversial. A recent study in older children and adolescents receiving HSCT from HLA-identical sibling donors has revealed higher mortality after peripheral blood stem cell (PBSC) compared to bone marrow (BM) transplantation (Eapen et al, JCO, 2004). However, despite the increasing use of PBSC in pediatric HSCT from matched unrelated donors (MUD), comparative studies on the relative risks and benefits of both stem cell sources are lacking. We therefore analysed the outcome of unrelated PBSC (n=118) and BM (n=102) transplants reported to the German/Austrian Pediatric Registry for Stem Cell Transplantation (PRST) between 1998 and 2003. Patients with hematologic malignancies (ALL, AML, CML, or MDS), who had received unmanipulated HSCT from ≥ 5/6 HLA antigen-matched unrelated donors following myeloablative conditioning were included into the analysis. PBSC and BM groups were comparable with regard to sex, age, CMV serostatus, GvHD prophylaxis, disease status at transplant, prophylactic growth factor use and degree of HLA-matching, while differences were detected in disease category (more MDS patients in PBSC group, p=0.02), transplanted cell dose (higher CD34-cell graft content in PBSC group, p=0.001) and median year of transplant (PBSC transplantations were more recent, p=0.01). Engraftment was achieved significantly faster after PBSC compared to BM transplantation: 15 vs. 19 days for neutrophil engraftment (p=0.001) and 21 vs. 25 days for platelet engraftment (p<0.01). The rate of acute GvHD grade II–IV (PBSC vs. BM: 44% vs. 39%, p=0.48) and severe acute GvHD Grade III/IV (29% vs. 21%, p=0.17) did not significantly differ between both groups. Moreover, the incidence of chronic GvHD (PBSC vs BM: 35% vs 33%, p=0.9) and extensive chronic GvHD (18% vs 18%, p=0.85) was identical at 3 years post transplant. In the PBSC group there was a statistically non-significant trend towards a higher risk for treatment-related mortality (PBSC vs BM: 34% vs 25%, p=0.14) and a lower risk for death of disease (PBSC vs. BM: 14% vs. 23%, p=0.16). However, this did no translate into a survival difference. With a median follow up of 2.9 years (PBSC) and 3.1 years (BM) overall survival (PBSC vs. BM: 50±5% vs. 46±6%; p=0.63) and event-free survival (45±5% vs. 44±6%; p=0.59) is comparable between both groups. This clinically most relevant result was confirmed in a multivariate analysis showing that advanced disease status at transplant (RR 2.4, 95%-CI 1.5–3.8, p=0.001) is a significant, independent risk factor for treatment failure, while the stem cell source (PBSC vs BM) has no effect (RR 1.1, 95%-CI 0.7–1.6, p=0.8). In summary, our data provide first evidence from a large, registry based analysis, that in pediatric recipients of MUD transplantation the use of PBSC instead of BM is not associated with inferior survival. Therefore, PBSC is a valid alternate stem cell source for pediatric HSCT from MUDs.

Immune reconstitution after purified autologous and allogeneic blood stem cell transplantation compared with unmanipulated bone marrow transplantation in children

Immune reconstitution is critical for the long-term success of haematopoietic stem cell transplantation (HSCT). We prospectively analysed immune reconstitution parameters after transplantation of autologous (group 1; n = 10) and allogeneic (group 2; n = 12) highly purified CD34+ peripheral blood stem cells (PBSC) and unmanipulated allogeneic bone marrow (BM) (group 3; n = 9) in children. Median follow-up after HSCT was 56 (group 1), 61 (group 2), and 40.5 months (group 3). Median CD34-cell dose transplanted in the three groups was 9.4 x 10(6)/kg, 20.3 x 10(6)/kg, and 4.25 x 10(6)/kg recipient's body weight (BW) respectively. Complete haematopoietic engraftment was seen in all patients without any significant differences between the three groups. T-cell reconstitution at 6 months was significantly delayed in autologous peripheral blood stem cell transplantation (PBSCT) compared with allogeneic BM transplantation (P < 0.028) and allogeneic PBSCT (P < 0.034). At 3 months after transplantation numbers of CD56+/3- natural killer cells were higher in the allogeneic PBSC group (P < 0.01) compared with the BM group. The numbers of proven bacterial and viral infections were equally distributed between the three groups. In conclusion, recipients of allogeneic highly purified CD34+ PBSC or unmanipulated BM have higher lymphocyte subset counts at 6 months after transplantation than recipients of autologous CD34-selected PBSC. Infection rates and outcome, however, were not significantly different.

Autologous hematopoietic stem cell transplantation for adults with acute myeloid leukemia in complete remission: The Edouard Herriot hospital experience

We retrospectively assess the long-term outcome and determined prognostic factors correlated with outcomes in adults with acute myeloid leukemia (AML) undergoing autologous hematopoietic stem cell transplantation (HSCT) in our institution over a 19-year period. A total of 78 adults who received autologous HSCT for AML in first complete remission (CR) and of 21 adults in further CR were included in the study. Bone marrow (n = 14) or peripheral blood stem cells (PBSC) (n = 85) transplantation was performed at a median of 2.9 months from CR. Hematologic recovery was significantly reduced in the PBSC group. Five-year cumulative incidences of relapse were 56 and 49%, respectively. Corresponding 5-year probabilities of event-free survival (EFS) were 33 and 35%, while those of overall survival (OS) were 38 and 49%, respectively. In multivariate analyses, cytogenetics was the main prognostic factor for outcome. Treatment-related mortality (TRM) was of 15% at 5 years, but higher in females as compared to males (p = 0.04). We confirmed that long-term EFS can be achieved after autologous HSCT in adult patients with AML. Results in adults who experience a relapse after conventional chemotherapy support the use of autologous HSCT as salvage therapy if such patients achieve a subsequent CR.

Similar Survival after Bone Marrow Versus Peripheral Blood Stem Cell Transplantation from Matched Unrelated Donors in Children with Hematologic Malignancies.

Peripheral blood stem cells (PBSC) are increasingly used instead of bone marrow (BM) for allogeneic haematopoietic stem cell transplantation (alloHSCT) in children. Prior studies in adults have suggested a comparable outcome with both stem cell sources in matched unrelated donor (MUD) transplantation. However, relative benefits of PBSC versus BM transplantation may substantially differ in children and adults due to a greater propensity to GvHD in older patients and a higher proliferation rate of blasts in childhood leukemia. Here we present the first comparison of the outcome following PBSC vs. BM transplantation from HLA-matched unrelated donors in an entirely pediatric cohort. Between 1992 and 2004, a total of 61 pediatric patients (pts) with haematologic malignancies underwent PBSC (n=38) or BM (n=23) transplantation from ≥ 5/6 HLA antigen-matched unrelated donors following myeloablative conditioning at our institution. PBSC and BM groups were comparable with regard to GvHD prophylaxis, disease category, disease status at transplant and recipient age, while differences were detected in recipients sex (more male pts in PBSC group, p=0.06), conditioning regimen (more busulfan-based conditioning in PBSC group, p=0.01) and median year of transplant (PBSC transplantations were more recent, p=0.001). Engraftment was achieved significantly faster after PBSC compared to BM transplantation (p=0.001). Median time to neutrophil engraftment was 18 (range: 9–28) and 24 (14–43) days for the PBSC and BM cohort, respectively. The rate of acute GvHD grade III/IV (PBSC vs. BM: 28.9% vs. 19.0%, p=0.54) and chronic GvHD (63.0% vs. 56.3%, p=0.75) was comparable between both groups. While there was a statistically non-significant trend towards increased risk of clinically extensive chronic GvHD following PBSC transplantation (48.1% vs. 25.0%, p=0.2), this did not translate into any detectable difference in treatment-related mortality (PBSC vs. BM: 28.9% vs. 26.1 %) or death of disease (21.7% vs. 21.1%) (p=1.0). With a median follow up of 3.4 years (PBSC) and 10.0 years (BM) overall survival (PBSC vs. BM: 47.5 ± 8.6 % vs. 51.8 ± 10.5 %; p = 0.88) and event-free survival (43.3 ± 8.3 % vs. 51.8 ± 10.5 %; p = 0.60) is without detectable difference between both groups. This result was confirmed in a multivariate analysis including stem cell source, recipient age, recipient sex, conditioning regimen, disease status at transplant and year of transplant as covariates, showing that advanced disease status at transplant is the only significant, independent risk factor for overall mortality (RR 2.4, 95%-CI 1.1–5.2, p=0.02). In conclusion, our data provide evidence that in pediatric recipients of MUD transplantation the use of PBSC instead of BM leads to a faster neutrophil engraftment and a trend towards higher incidence of extensive chronic GvHD. As overall survival and event-free survival is comparable when using PBSC and BM, PBSC is a valid alternate stem cell source for pediatric alloHSCT from MUDs. Supported by the Elterninitiative Kinderkrebsklinik e.V., Duesseldorf

Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors

AbstractThe long-term follow-up of a study including 214 patients receiving either peripheral blood stem cells (PBSCs) or bone marrow (BM) from an HLA-A, -B, and -DR–compatible unrelated donor is presented. Median follow-up was 4.4 (2.3-7.3) and 5.0 (0.7-8.4) years in the 2 groups, respectively. Cumulative incidence of overall chronic graft-versus-host disease (GVHD) was similar in the 2 groups (78% vs 71%), while extensive chronic GVHD was significantly more common in the PBSC group compared with the BM group (39% vs 24%, P = .03). The 5-year transplant-related mortality (TRM) was 37% in the PBSC group and 35% in the BM controls (P = .7), and overall survival was 42% in both groups. The relapse incidences were 26% and 27% in the 2 groups, respectively, resulting in a disease-free survival of 41% in both groups. In conclusion, PBSCs from HLA-compatible unrelated donors results in similar outcome compared to BM but implies an increased risk for extensive chronic GVHD.

Peripheral Blood Stem Cells vs Bone Marrow for Matched Sibling Transplant in AML and ALL in First Remission.

We report a retrospective comparison of peripheral blood (PBSC) versus bone marrow derived stem cells for allogeneic transplant in a cohort of similarly treated patients based on eight year data from a single institution. Over the period 1995 to 2003, a total of 151 patients with AML or ALL in first CR underwent allogeneic matched sibling donor transplant, 98 AML patients and 53 with ALL. The source of stem cells was bone marrow in 69, G-CSF mobilized peripheral blood stem cells (PBSC) in 82. Of the AML patients, 40 (58%) received marrow, 58 (71%) received PBSC. Of the ALL patients, 29 (42%) received marrow, 24 (29%) got PBSC. The age of patients receiving marrow was 32.7 ± 13.6, and for those getting PBSC was 36.1 ± 16.1. The conditioning regimen was fully ablative (TBI/VP-16) in all but five patients (Fludarabine/Melphalan in 1 marrow and 4 PBSC pts). GVHD prophylaxis was with cyclosporine/methotrexate in patients receiving ablative conditioning, and CSP/MMF in the flu/mel patients.The time to achieving an ANC >1000 was significantly shorter (P value=.0001) in the PBSC group, 18.2 ±6.6 days vs. 27.2 ±48.7 in the marrow group. Time to achieving a platelet count greater than 25K was significantly shorter (P value=2x10−11) for the PBSC group, 20.9 ± 8.5 vs. 31.8 ± 11.2 for marrow. This was true as well for time to reach platelet counts greater than 100K (P value=10−8), 29.7 ± 28 days for PBSC, 55.8 ±55.6 for marrow. In fact there was a significant increase (P=.0001) in the number of patients, 29 (42%) of marrow recipients vs 11 (13%) of PBSC, who did not at any time achieve a platelet count of >100K. There was no significant difference in survival at 2 years or 4 years between marrow or PBSC-Kaplan-Meier survival probability at 2 and 4 years respectively for AML was.66 and.54 for marrow, and.67 and.54 for PBSC. In ALL, the 2 and 4 year K-M survival probability was.72 and.65 for marrow;.69 and.69 for PBSC recipients. There was no significant difference in acute GVHD, with grade I-II described in 19 (28%) of the marrow pts, 29 (35%) in the PBSC pts, and grade II-IV in 8 (12%) marrow pts and 11 (13%) receiving PBSC (p value =.57), or chronic GVHD (P value=.62). Interestingly, in a subset analysis of patients who were diagnosed with acute GVHD, there was a significant difference in disease free survival at 5 years (see graph), suggesting that there is a qualitative difference between acute GVHD observed as a result of bone marrow versus PBSC as a source of stem cells. [Display omitted]

Hickman catheter site infections after allogeneic stem cell transplantation: a single-center experience

Hickman catheter site infections are known to increase transplant-related mortality. A retrospective analysis of 103 patients who received allogeneic stems cell transplants was performed to define the incidence and outcomes of Hickman infections. Seventy-six patients received peripheral blood stem cells (PBSC) (73.8%) and 29 patients (28.2%) nonmyeloablative conditioning. During the median follow-up of 9 months, Hickman infections were observed in 10 patients (9.7%) at a median onset of 32 days posttransplant (range 2 to 102 days). The causative organisms identified in five cases included Staphylococcus species ( n = 4) and Pseudomonas aeruginosa ( n = 1). Six events successfully resolved with antibiotic treatment, while the other four required the removal of the Hickman catheter with subsequent death in two cases. The survival duration for infected patients was shorter than that for the noninfected group (83 days vs 366 days, P < .001). Myeloid engraftment was delayed in the infected group (18.0 days vs 15.0 days, P = .038) and this complication was more frequently observed among the BMT compared with PBSC group (22.2% vs 5.3%, P = .019). Hickman infections were associated with transplant-related mortality especially during the first 3 months posttransplant. As such, the current results emphasize both the importance of Hickman catheter care and the need for surveillance cultures after stem cell transplantation.

High-dose thiotepa and etoposide in children with poor-prognosis brain tumors.

Outcome data were analyzed for 27 patients who were affected with recurrent or newly diagnosed high-risk brain tumors and who underwent high-dose chemotherapy with triethylenethiophosphoramide (thiotepa) and etoposide in addition to autologous stem cell transplantation between May 1992 and September 2002. Fifteen males and 12 females (median age, 11 years) were included in the study. Twelve patients had newly diagnosed high-risk brain tumors, and 15 patients had recurrent brain tumors. The conditioning regimen consisted of thiotepa 900 mg/m2 and etoposide 1500 mg/m2 over 3 days starting on Day -5. Stem cell rescue was performed using bone marrow (BM) in 8 patients, peripheral blood stem cells (PBSCs) in 18 patients, and BM and PBSCs in 1 patient. For the BM group, neutrophil (PMN) engraftment was achieved on Day +14 (median value), whereas platelet (PLT) engraftment was achieved on Day +68 (median value). One patient did not achieve PLT engraftment. For the PBSC group, the PMN engraftment was achieved on Day +10.0 (median value), and the PLT engraftment was achieved on Day +15.5 (median value). Transplantation-related toxicity (evaluated using the Bearman score) included Grade 2-3 mucositis in 16 patients, Grade 1 kidney toxicity in 6 patients, Grade 1 liver toxicity in 6 patients, and Grade 2 liver toxicity in 1 patient. Transplantation-related mortality was observed in 1 patient (3.6%), who died of Candida pneumonia. The 3-year overall survival (OS) rate was 44.6%, and the 3-year event-free survival (EFS) rate was 31%. There was a statistically significant difference in OS and EFS rates for patients who underwent ASCT and achieved complete remission compared with patients who had measurable disease. The results of the current study suggest that high-dose chemotherapy followed by ASCT may be beneficial for patients who achieve complete remission before ASCT, whereas for other patients, new strategies are required.

Autologous stem cell transplantation for acute myelogenous leukemia in first complete remission: a 6-year follow-up study of 101 patients from a single institution

The objective of the study was to assess the long-term outcome and impact of stem cell source in patients with acute myelogenous leukemia (AML) who received ASCT in first complete remission (CR). A total of 101 patients (median age 46 years) were included in the study. Cytogenetic categories distribution was: favorable: 18%, intermediate: 42%, and unfavorable: 7%. More than one induction course was needed for CR in 21% of patients. In all, 78% of patients had received at least one course of high-dose ara-C before autologous stem cell transplantation (ASCT). Bone marrow (n=58) or peripheral blood stem cells (PBSC) (n=43) transplantation was performed at a median of 3.5 months from CR. Hematologic recovery and hospitalization duration were significantly reduced in the PBSC group. No toxic death was recorded in this group. The median follow-up of survivors is 67 months (range: 15-183). The 6-year survival, disease-free survival (DFS), and relapse probabilities are 44%, 38%, and 54%, respectively. The presence of a favorable karyotype and the use of PBSC are independently associated to better survival, and DFS by multivariate analysis. Our results confirm that long-term DFS can be achieved with high-dose chemotherapy and ASCT in patients with AML. They show that use of PBSC is associated to very low mortality rate and acceptable morbidity and contributes to an improvement of autotransplant results.

Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study

AbstractThe use of peripheral blood stem cells (PBSCs) is rapidly growing in the allogeneic transplantation setting as an alternative to bone marrow (BM). We previously reported a higher incidence of chronic graft-versus-host disease (cGVHD) associated with allogeneic PBSC transplantation in a randomized trial. In this follow-up report, we analyzed the evolution of cGVHD in the patients (n = 101) enrolled on this study. At a median follow-up of 45 months (range, 31-57 months), we found that the 3-year cumulative incidence of cGVHD was 65% (95% confidence interval [CI] 51%-78%) in the PBSC group and 36% (95% CI 23%-49%) in the BM group (P = .004). We also found that extensive cGVHD was more frequent in the PBSC group (44% [95% CI 30%-58%] vs 17% [95% CI 7%-27%];P = .004). The prevalence of cGVHD was always higher in the PBSC arm. Ocular involvement was more frequent in PBSC recipients (P = .02). Cutaneous and liver involvement was similar among BM and PBSC recipients. Chronic GVHD required multiple courses of immunosuppressive therapy in addition to cyclosporine and corticosteroids during longer periods (P = .03). Altogether, this translated into longer periods of hospitalization after transplantation in the PBSC group (P = .04). Finally, we also confirm that cGVHD after PBSC transplantation is associated with an antileukemic effect that is at least as potent as after BM. However, to date, this has not translated into a survival difference, possibly due to the early-stage leukemic status of these patients or to the relatively small size of the study population.

No difference in graft-versus-host disease, relapse, and survival comparing peripheral stem cells to bone marrow using unrelated donors

AbstractThe clinical results in 107 patients receiving a peripheral blood stem cell (PBSC) graft mobilized by granulocyte colony-stimulating factor (G-CSF) from HLA-A, -B, and -DR–compatible unrelated donors were compared to 107 matched controls receiving unrelated bone marrow (BM) transplants. Engraftment was achieved in 94% of the patients in both groups. The PBSC graft contained significantly more nucleated cells, CD34+, CD3+, and CD56+ cells (P < .001), and resulted in a significantly shorter time-to-neutrophil (15 versus 19 days) and platelet engraftment (20 versus 27 days), compared to the BM control group (P < .001). Probabilities of acute graft-versus-host disease (GVHD) grades II to IV were 35% and 32% (not significant [NS]) and of chronic GVHD 61% and 76% (NS) in the PBSC and BM groups, respectively. There was no difference between the 2 groups in bacteremia, cytomegalovirus reactivation or disease, and fungal infection. The 3-year transplant-related mortality (TRM) rates were 42% in the PBSC group and 31% in the BM controls (P = .7) and the survival rates were 46% and 51%, respectively. The probability of relapse was 25% and 31% in both groups (NS), resulting in disease-free survival rates of 43% in the PBSC group and 46% in the BM controls (NS). In the multivariate analysis, early disease, acute GVHD grade 0 to I, and presence of chronic GVHD were independent factors associated with a better disease-free survival in this study. PBSC from HLA-compatible unrelated donors can be used safely as an alternative to BM for stem cell transplantation.

Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial

Autologous transplantation with peripheral blood stem cells (PBSC) results in faster haematopoietic-cell repopulation than with bone marrow. We prospectively compared bone marrow and PBSC for allogeneic transplantation. Adult HLA-identical sibling donors provided bone marrow and lenograstim-mobilised PBSC. 39 patients with malignant haematological disorders were infused with either bone marrow (n=19) or PBSC (n=20) after standard conditioning regimens in a double-blind, randomised fashion. The identity of the infused products for all patients remained masked until 1 year after the last patient had received transplantation. The PBSC group had significantly faster neutrophil recovery to 0.5x10(9)/L (median 17.5 vs 23 days, p=0.002), and platelet recovery to 20x10(9)/L (median 11 vs 18 days, p<0.0001) and to 50x10(9)/L (median 20.5 vs 27 days, p=0.02) than the bone-marrow group. PBSC patients were discharged from hospital earlier than were bone-marrow patients (median 26 vs 31 days, p=0.01). At 4 weeks after transplantation, absolute lymphocytes (0.48 vs 0.63, p=0.08) and CD25 cells (0.04 vs 0.08, p=0.007) were higher in the PBSC group, and the proportion of patients with absolute lymphopenia (74% vs 33%, p=0.03) and CD4 lymphopenia (59% vs 24%, p=0.05) was significantly higher in the bone-marrow group. There was no significant difference in the occurrence of acute or chronic graft-versus-host disease and overall survival. The probability of relapse was significantly higher in the bone-marrow group than in the PBSC group (p=0.01); all five relapses occurred among bone-marrow recipients. Our small study indicates that PBSCs are better than bone marrow for allogeneic transplantation from HLA-identical siblings in terms of faster haematopoietic and immune recovery, and have the potential to reduce disease recurrence.