Peripheral Blood Progenitor Cell Transplantation Research Articles

Romiplostim After Autologous Peripheral Blood Progenitor Cell Transplantation: Results of a Pilot Study

Romiplostim After Autologous Peripheral Blood Progenitor Cell Transplantation: Results of a Pilot Study

Peripheral Blood Progenitor Cell (PBPC) Transplantation from Haploidentical Donors Following Reduced Intensity Conditioning (RIC) for High-Risk Hematologic Malignancies

Peripheral Blood Progenitor Cell (PBPC) Transplantation from Haploidentical Donors Following Reduced Intensity Conditioning (RIC) for High-Risk Hematologic Malignancies

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.

Graft Source and HLA-Matching Degree-Based Analyses of Long-Term Outcomes of Unrelated Donor Transplants in Adult High-Risk Acute Lymphoblastic Leukemia: Similar Outcomes Between Bone Marrow and Peripheral Blood Progenitor Cells Transplants,

Abstract 4167 Background:Adults with high-risk acute lymphoblastic leukemia (ALL) have a poor outcome with standard chemotherapy and usually undergo unrelated donor stem cell transplantation (URD-SCT) if a matched sibling donor is not available. However, long-term results of URD-SCT, especially based on HLA-matching degree and graft source, are scarce in adult high-risk ALL. To assess the effect of HLA-matching degree and graft source, we analyzed long-term outcomes of 109 consecutive URD transplants with adult high-risk ALL (2000–2008). Method:Using allele-level typing, graft sources were classified as 8/8-matched bone marrow (BM; n=31), 8/8-matched peripheral blood progenitor cells (PBPC; n=19), 7/8-matched BM (n=35), and 7/8-matched PBPC (n=24). Patients received total body irradiation (≥12 Gy)-based full-intensity (n=95) or reduced-intensity (fludarabine plus melphalan; n=14) conditioning regimens. All patients received the same graft-versus-host disease prophylaxis consisting of tacrolimus plus methotrexate. Antithymocyte globulin was administered to all 7/8-matched transplants. Result:After a median follow-up of 57 months, the 5-year cumulative incidence of relapse was 19% for 8/8-matched BM, 16% for 8/8-matched PBPC, 37% for 7/8-matched BM, and 48% for 7/8-matched PBPC (P=0.013). Conversely, no significant difference in the 5-year cumulative incidence of non-relapse mortality was observed between each group of patients. Consequently, disease-free survival (DFS) at 5 years was inferior using 7/8-matched BM (46%) or 7/8-matched PBPC (42%), compared with 8/8-matched grafts (65% for BM and 58% for PBPC) (P=0.044). However, when considering pre-transplant disease status and conditioning intensity, no influence of HLA-matching degree and graft source on outcomes was found in transplants receiving full-intensity conditioning in first complete remission (CR1). Notably, outcomes were similar between BM and PBPC transplants in each group of patients showing the same HLA-matching degree. Regardless of HLA-matching degree and graft source, pre-transplant disease status (CR1 versus >CR1) was an independent predictive factor affecting relapse (RR 3.09, P=0.005) and DFS (RR 2.69, P=0.003). The absence of chronic graft-versus-host disease was also associated with higher relapse (RR 5.60, P<0.001) and poorer DFS (RR 2.49, P=0.005). Conclusion:Our long-term data suggest that outcomes are similar for transplantation using BM or PBPC in the setting of 8/8-matched or 7/8-matched URD-SCT in adult high-risk ALL. Disclosures:No relevant conflicts of interest to declare.

Impact of Constitutional Polymorphisms in VCAM1, CD44, CXCL12, CXCR4 and CSF3R in Progenitor Cell Mobilization in Patients with Hematological Malignancies

Abstract 2997Introduction. The identification of genetic variants predictive of response to G-CSF mobilization might be useful in deciding the best strategy to obtain haematopoietic progenitors (HP) in patients scheduled for autologous peripheral blood progenitor cell transplant. Recently, one study has demonstrated the relationship among polymorphisms in genes implicated in trafficking and homing of CD34+ cells and the degree of mobilization after G-CSF therapy among healthy donors (Haematologica 2011; 96: 102–109). Aims. To evaluate if polymorphisms in five genes (CD44 rs13347 C>T, CSF3R rs3917924 A>G, CXCR4 rs2680880 A>T, CXCL12 rs1801157 G>A, and VCAM1 rs1041163 T>C) previously associated with the number of G-CSF mobilized CD34+ cells in healthy donors, can also predict the mobilization efficacy in a group of patients with hematological malignancies. Patients and Methods. We retrospectively evaluated 183 patients who were treated with s.c. G-CSF at 10 mcg/kg during 4 days. HP collection was initiated or not at day 5 according to the CD34+ number in peripheral blood (PB). Patients were selected among two groups: (1) poor mobilizers (n=109), who failed a mobilization attempt, presenting with <10 CD34+cells/mcl of PB, and (2) good mobilizers (n=74), those achieving >2 ×106CD34+ cells/kg in a first and only apheresis. The genetic variants were genotyped by allelic discrimination polymerase chain reaction (PCR) assays using TaqMan®Genotyping Assays (Applied Biosystems). Results. Patients diagnosed with lymphoma, myeloma and acute leukaemia were 40%, 38% and 21% of poor mobilizers, and 38%, 46% and 16% of good mobilizers, respectively. On the overall group, the genetic variant TT rs1801157 in CXCL12 was significantly associated with poor mobilization (p=0.040). Among lymphoma patients, the presence of the C allele in VCAM1 was significantly associated with mobilization rate (49% vs 19% among poor and good mobilizers respectively, p=0.011). In this lymphoma group, a trend towards poor mobilization was also observed in relation with homocygosis for the T allele of CXCL12 (12% vs 0% in poor and good mobilizers, respectively, p=0.066). The analyzed variables had no impact on the mobilization capacity in patients with myeloma or acute leukaemia. Discussion. Genetic variants in VCAM and CXCL12 seem to be related with the mobilization yield after G-CSF, particularly in lymphoma patients. Other polymorphisms in adhesion molecules related to the degree of CD34+ cell mobilization in healthy donors have not shown a relevant role in patients with hematological malignancies, probably reflecting the predominant effect of disease biology and/or of previous treatments.Funding. This study was supported in part by a research grants 04515/GERM '2f 06; RECAVA RD06/0014/0039, and FIS 10/02594 Disclosures:No relevant conflicts of interest to declare.

Treatment of Myelofibrosis Using I.V. Treosulfan and Autologous Peripheral Blood Progenitor Cell Transplantation Is Feasible and Results in Hematologic Responses – Long-Term Follow-up and Final Analysis of a One-Armed Clinical Study and of Individual Cases

Abstract 4514 Introduction:Myelofibrosis with myeloid metaplasia is a chronic myeloproliferative disorder. The only curative therapy to date is myeloablation followed by allogeneic transplantation. Autologous transplantation after myeloablation with high-dose oral busulfan provides a palliative approach which might lead to a long-term relief of symptoms of the disease and is associated with acceptable morbidity and mortality (Anderson et al., Blood, 2001; 98:586–593). However, busulfan pharmacokinetics after oral administration can vary among patients. On the other hand treosulfan, a bi-functional alkylating drug, can be administered safely i.v. with reliable pharmacokinetics and might be suitable for conditioning of patients with myelofibrosis. Methods and Results:In a pilot phase, we treated three patients on an individual basis with an autologous transplantation after myeloablation with treosulfan. Following the encouraging results we initiated a clinical trial. Included were patients with myelofibrosis and a high risk disease according to the 1997 criteria of Cervantes. The study is registered at www.kompetenznetz-leukaemie.de.As of today we have transplanted 11 patients according to the protocol, 9 in Heidelberg, 1 at the Diakoniekrankenhaus Rotenburg and 1 at the University Hospital Rostock. Age at transplantation ranged from 50 to 69 years. For 10 of 11 patients we have been successful in collecting more than 5×106 CD34+ cells/kg body weight (one patient with 4,9 ×106) after mobilization with G-CSF at 16 μg/kg BW s.c. daily for 4 days. The conditioning regimen was treosulfan for three days (total dose 42 g/m2). Hematologic reconstitution was considerably protracted with a median of 26 days (leucocyte count > 1/nl) compared to autologous transplantation for other indications. One patient died on day 34 post transplantation after cerebral hemorrhage. He suffered from severe transfusion refractory thrombocytopenia already before the transplantation.The twelve-month follow-up showed symptomatic relief, mostly as freedom from transfusions in 7 of 11 patients. The two survivors are alive after 9 years, one with allogeneic transplantation 2 years and the other with allogeneic transplantation 8 years after autologous transplantation. The median survival of the other 9 patients was 3.5 years after autologous transplantation (0.1 – 7.5 years). Conclusions:We conclude that myeloablation with treosulfan and autologous PBPCT for patients with myelofibrosis can provide significant palliation. It is associated with an acceptable morbidity and mortality, taking into account the high-risk nature of the disease. The approach is feasible for high-risk patients that cannot or chose not to undergo allogeneic transplantation. Disclosures:Buss:medac GmbH: Research Funding. Off Label Use: Treosulfan, off-label use as an agent for high-dose chemotherapy with subsequent autologous stem cell transplantation. Topaly:medac GmbH: Research Funding. Fruehauf:medac GmbH: Research Funding.

Ex vivo graft purging and expansion of autologous blood progenitor cell products from patients with multiple myeloma.

Autologous peripheral blood progenitor cell (PBPC) transplantation is the treatment of choice for selected myeloma patients. However, tumor cells contaminating the apheresis product are a potential source of relapse. Here we report a sequential purging strategy targeting mature and immature clonogenic myeloma cell populations in the autograft. Thawed PBPC products of myeloma patients were treated with rituximab to kill CD138(-)20(+) B cells (highly clonogenic immature cells), and bortezomib to target CD138(+) cells (normal and differentiated myeloma plasma cells), followed by coculture with allogeneic mesenchymal stem cells (MSC) from normal donors. After 7 days of coculture, nonadherent cells were removed and cultured in the absence of MSC for an additional 7 days. Then, efficacy of purging (removal of CD138(-)20(+) and CD138(+) cells) was assessed by flow cytometry and PCR. We used our ex vivo purging strategy to treat frozen aphereses from 16 patients. CD138(+) and CD138(-)20(+)(19(+)) cells present in the initial products were depleted more than 3 and 4 logs, respectively based on 10(6) flow-acquisition events, and to levels below the limit of detection by PCR. In contrast, total nucleated cell (TNC), CD34(+) cell, and colony-forming cell numbers were increased by approximately 12 to 20, 8-, and 23-fold, respectively. Overall, ex vivo treatment of apheresis products with rituximab, bortezomib, and coculture with normal donor MSC depleted mature and immature myeloma cells from clinical aphereses while expanding the normal hematopoietic progenitor cell compartment.

Hematologic Changes After Total Body Irradiation and Autologous Transplantation of Hematopoietic Peripheral Blood Progenitor Cells in Dogs With Lymphoma

Dogs with and without lymphoma have undergone hematopoietic cell transplantation in a research setting for decades. North Carolina State University is currently treating dogs with B- and T-cell lymphoma in a clinical setting with autologous peripheral blood progenitor cell transplants, using peripheral blood CD34+ progenitor cells harvested using an apheresis machine. Complete blood counts were performed daily for 15 to 19 days posttransplantation to monitor peripheral blood cell nadirs and subsequent CD34+ cell engraftment. This study documents the hematologic toxicities of total body irradiation in 10 dogs and the subsequent recovery of the affected cell lines after peripheral blood progenitor cell transplant, indicating successful CD34+ engraftment. All peripheral blood cell lines, excluding red blood cells, experienced grade 4 toxicities. All dogs had ≥ 500 neutrophils/μl by day 12, while thrombocytopenia persisted for many weeks. All dogs were clinically normal at discharge.

Higher Doses of CD34+ PBPC are Associated With a Rapid Acquisition of Full Donor Chimerism and Lower Risk of Relapse After Allogeneic Transplantation in Pediatric Patients With Hematological Malignancies

We conducted a retrospective study assessing the predictive value of early full donor chimerism status for relapse after allogeneic peripheral blood progenitor cell transplantation in 40 children aged between 1 and 16 years (median 8) with leukemia. The only variable that had a significant influence on chimerism status in either univariate or multivariate analysis was the number of CD34 cells infused. We found that the patients who were in complete donor chimerism by day +30 had a lower probability of relapse than those who were not (14% ± 6% versus 54% ± 15%; HR, 5.24; 95% confidence interval, 2.10-43.63; P = 0.003). Mixed chimerism by day +30, absence of chronic GvHD, and advanced disease at transplantation were significant risk factors for relapse in our patients. Children who presented early complete chimerism had a probability of developing chronic graft versus host disease significantly higher than patients with mixed chimerism (P = 0.04). Therefore, the analysis of chimerism kinetic in children undergoing peripheral blood progenitor cell transplantation would permit an early identification of patients at risk of relapse and patients with high risk of developing chronic graft versus host disease.

High-dose Busulfan and Cyclophosphamide as a Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation in Childhood Non-Hodgkin Lymphoma Patients

We analyzed the outcome in 22 children with refractory or relapsed non-Hodgkin lymphoma who underwent autologous peripheral blood progenitor cell transplantation between 1994 and 2009. The conditioning regimen used in all patients consisted of busulfan and cyclophosphamide. Median age was 6 years (range 2 to 16 y). The most common histologic subtype was Burkitt lymphoma. Ten patients were in complete remission and 12 in partial remission at the time of transplant. The median dose of CD34+ cells that was infused was 4.6 × 10/kg (range 2.1 to 58.7 × 10/kg). All the patients were engrafted, with a median time for neutrophils and platelets recovery of 11 (range, 8 to 15 d) and 14 (range, 9 to 60 d) days, respectively. Nonhematologic treatment-related toxicity included severe mucositis in 3 patients and hepatic sinusoidal obstruction syndrome in 1 patient. There were no transplant-related mortalities. With a median follow-up of 60 months (range, 4 to 180 d) the disease-free survival was 90 ± 6.5% for the whole group. This retrospective study shows a high long-term survival using busulfan/cyclophosphamide as conditioning regimen in children with refractory or relapsed non-Hodgkin lymphoma.

High-Dose Busulfan and Melphalan as Conditioning Regimen for Autologous Peripheral Blood Progenitor Cell Transplantation in High-Risk Neuroblastoma Patients

The aim of this retrospective study was to analyze the outcome and identify risk factors associated with progression-free survival (PFS) in 36 children with high-risk neuroblastoma who underwent autologous peripheral blood progenitor cell (PBPC) transplantation between 1994 and 2010. The conditioning regimen used in all cases consisted of high-dose of busulfan and melphalan. Median age at transplantation was 3 years (range: 0.7–14 years). The median times to neutrophil and platelet engraftment were 11 days (range: 9.16 days) and 13 days (range: 9.33), respectively. Twenty-one patients developed nonhematologic toxicity: 15 patients had mucositis, 4 patients developed an engraftment syndrome, and there were 2 cases of liver toxicity. No toxic deaths were observed. There were 15 patients who relapsed. The median time to relapse was 6 months after the transplant (range: 3–13 months). With a median follow-up of 55 months (range: 4–180 months), the PFS was 57% ± 8.5% for the whole group. In multivariate analysis, age below 3 years (P < .005), complete remission (CR) pretransplantation (P < .07) and 1p germline status (P < .01) were variables associated with better outcomes. Patients who were or achieved early CR following transplantation (3 months posttransplantation) had a probability of PFS of 91% ± 6% as compared to patients who did not (PFS 9% ± 8%) (P < .0001). This retrospective study shows that high dose of busulfan and melphalan as conditioning regimen in children with high-risk neuroblastoma is associated with very low morbidity and no mortality in the authors’ hands. Younger patients with no 1p deletions and in first CR at transplantation had the better outcome.

Leuprolide Acetate (GnRH Agonist) to Enhance Immune Function Post-Autologous Hematopoietic Stem Cell Transplantation (HSCT)

AbstractAbstract 4292High-dose chemotherapy with autologous HSCT results in profound immunodeficiency early post transplant. Immune reconstitution is largely derived from the transplanted stem cells and occurs over a period of many months. Sex steroid hormones (testosterone and estrogen) have been shown to inhibit thymic function. Castration and sex steroid inhibition have been reported to stimulate thymic regeneration and production of T-cells and also, improved bone marrow function. We performed a study to test the hypothesis that temporarily blocking production of sex hormones using leuprolide acetate, a gonadotropin hormone-releasing hormone [GnRH] agonist, would improve thymic function and accelerate immune reconstitution following autologous stem cell transplantation. Methods:Adult patients receiving myeloablative autologous peripheral blood progenitor cell transplantation for lymphoma, Hodgkin's disease or multiple myeloma were eligible. Females and males, age 18–50 and 18–65 years, respectively, were included. Patients were required to be in remission or have chemosensitive relapse. Patients could not have received mediastinal radiation, or recent testosterone or estrogen treatment, or post transplant therapy that would affect immune function. Patients were randomized to receive 3 intramuscular injections of leuprolide acetate (Lupron 11.25 mg 3 Month Depot) or placebo approximately 3 months apart to cover the period from the date of transplantation to 8 months post HSCT. The primary endpoint was in vitro antibody and T cell response to vaccination with keyhole limpet haemocyanin (KLH) at 6 months post-HSCT. Immunoglobulins were measured by ELISA and interferon-gamma (IFNγ) by ELISpot. Results:25 subjects (19 males and 6 females) were enrolled into the study at 3 sites. 13 were randomized to placebo and 12 to leuprolide treatment. As expected, suppression of luteinizing hormone and total testosterone was observed in males in the leuprolide acetate group at all evaluation time points during treatment (P<0.1 vs. placebo). There was no significant difference in time to engraftment or in the adverse events and transplant related toxicities experienced by the leuprolide or the placebo group. One subject in the leuprolide acetate group died during the study due to pneumonia after hematopoietic recovery, which was not considered related to study drug. Early disease progression occurred in one patient in the leuprolide acetate and 3 in the placebo group. The study was closed due to slow patient accrual.9 patients in each group completed 6 months on study. 8 patients in the leuprolide group and 5 in the placebo group received KLH vaccination and were evaluable for response one month later. There were significantly improved IgM and IgG1 responses in the leuprolide group; no significant difference was detected for IgG2, IgG3, IgG4 and IFNγ responses. The following table shows the difference in the assays performed prevaccination and 1 month post vaccination.The output of naïve T-cell subsets and the production of TCR rearrangement excision circles (TRECs) were determined at screening, and post HSCT. There was an increase in naïve CD4+ TREC positive cells at the 6 month time point consistent with renewed thymus function. Conclusion:Despite the limited number of patients, there was a trend to increased antibody responses to the de novo antigen KLH, which reached statistical significance for IgM and IgG1, reflecting increased primary and secondary immune responses. Another indicator of thymus function was the appearance of circulating naïve, TREC+ CD4+ cells at 6 months in the leuprolide acetate group. Further study of sex steroid inhibition is needed to fully establish the enhanced thymic function and immune reconstitution following HSCT. Disclosures:Off Label Use: Leuprolide (Lupron) to enhance immune recovery after stem cell transplantation. Jiang:Abbott: Employment, Equity Ownership. Chwalisz:Abbott: Employment, Equity Ownership. Mattia-Goldberg:Abbott: Employment, Equity Ownership. Sajwani:Abbott: Employment, Equity Ownership. Boyd:Norwood Immunology: Employment.

Effect of Stem Cell Source From Unrelated Donors on Transplant Outcomes In Severe Aplastic Anemia (SAA): a Comparison of Unrelated Bone Marrow (BM) and Peripheral Blood Progenitor Cells (PBPC)

AbstractAbstract 531Unrelated 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.

Comparison of Outcomes after Transplantation of G-CSF–Stimulated Bone Marrow Grafts versus Bone Marrow or Peripheral Blood Grafts from HLA-Matched Sibling Donors for Patients with Severe Aplastic Anemia

We compared outcomes of patients with severe aplastic anemia (SAA) who received granulocyte-colony stimulating factor (G-CSF)-stimulated bone marrow (G-BM) (n = 78), unstimulated bone marrow (BM) (n= 547), or peripheral blood progenitor cells (PBPC) (n = 134) from an HLA-matched sibling. Transplantations occurred in 1997 to 2003. Rates of neutrophil and platelet recovery were not different among the 3 treatment groups. Grade 2-4 acute graft-versus-host disease (aGVHD) (relative risk [RR] = 0.82, P = .539), grade 3-4 aGVHD (RR = 0.74, P = .535), and chronic GVHD (cGVHD) (RR = 1.56, P = .229) were similar after G-BM and BM transplants. Grade 2-4 aGVHD (RR = 2.37, P = .012) but not grade 3-4 aGVHD (RR = 1.66, P = .323) and cGVHD (RR = 5.09, P < .001) were higher after PBPC transplants compared to G-BM. Grade 2-4 (RR = 2.90, P < .001), grade 3-4 (RR = 2.24, P = .009) aGVHD and cGVHD (RR = 3.26, P < .001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05). These data suggest no advantage to using G-BM and the observed higher rates of aGVHD and cGVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA-matched sibling transplants for SAA.

Evaluation of a new cell separator for collection of peripheral blood CD34+ progenitor cells in pediatric patients

This study was conducted to evaluate the performance of the COM.TEC cell separator (Fresenius HemoCare GmbH) for collecting CD34+ cells in pediatric patients who were intended to have autologous peripheral blood progenitor cell transplantation, with respect to collection variables, prediction power of CD34+ cell yield, and influence on donors. A total of 26 pediatric solid tumor patients who received mobilization chemotherapy and granulocyte-colony-stimulating factor underwent CD34+ cell collection (n = 96) using the COM.TEC auto mononuclear cell (MNC) program. Patients were divided into a neuroblastoma (NBL) group and a brain tumor group according to the intensity of prior chemotherapy regimens. The collection variables, cellular variables of leukapheresis products, and the peripheral blood cell counts of patients were compared with those acquired using the COBE Spectra (GambroBCT). The CD34+ cell collection efficiency (CE) and the percentage ratios of actual to predicted CD34+ cell yield indicating prediction power were analyzed. Using the COM.TEC auto MNC program, the processing rate was higher and the product volume was smaller (p < 0.05) than those of the COBE Spectra. Platelet (PLT) reduction in peripheral blood and PLT contamination of the products were significantly lower (p < 0.01). The median CE was less than 60% in both patient groups (50.0 and 48.4%, respectively). The actual collected CD34+ cell yields were medians of 66.9 and 76.1% of the predicted values in NBL group and brain tumor group, respectively. PBPC collections by the COM.TEC cell separator had advantages of high processing rate, low product volume, and low contamination by PLTs of product. Low PLT loss was observed in pediatric patients who need to collect autologous PBPCs. However, applying CD34+ cell yield prediction was not practical for prospective scheduling of the next collection. More specified data need to be accumulated for more accurate prediction of CD34+ cell yield in pediatric patients.

Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis

Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate. We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia. Data were available on 1525 patients transplanted between 2002 and 2006. 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n=10), or mismatched at one (n=40) or two (n=115) antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n=632 and n=332, respectively), or mismatched at one locus (n=256 and n=140, respectively). Leukaemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (HR 1.62, 95% CI 1.18-2.23; p=0.003) or bone-marrow transplantation (HR 1.69, 95% CI 1.19-2.39; p=0.003). Grades 2-4 acute and chronic graft-versus-host disease (GvHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0.57, 95% 0.42-0.77; p=0.002 and HR 0.38, 0.27-0.53; p=0.003, respectively), while the incidence of chronic, but not acute GvHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0.63, 0.44-0.90; p=0.01). These data support the use of UCB for adults with acute leukaemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently.

Abstract 3722: Ovarian suppression with gonadotropin-releasing hormone analogues (Gn-RH) in high risk premenopausal breast cancer patients (PM-HR-BC): decrease of T regulatory cells (T-regs) and of vascular endothelial growth factor (VEGF)

Abstract Background: In a previous phase II study we have shown an improvement of disease-free survival and overall survival of 180 premenopauseal high-risk early breast cancer patients (PM-HR-BC) treated with ovarian suppression with Gn-RH and a chemotherapy tailored to the peculiar clinical situation. Aim of this study was the evaluation of VEGF and T-regs in a group of PM-HR-BC patients treated with the above mentioned therapy. Methods: From 01/2006 to 12/2008 54 patients with PM-HR-BC were entered into this study. At baseline, one week before chemotherapy, patients received a Gn-RH analogue which was continued for five years. Tailored adjuvant chemotherapy, included anthracycline and taxane based regimens. 11 patients with triple negative tumors, received a platinum-based consolidation high-dose chemotherapy with (n. 7) or without (n. 4) autologous peripheral blood progenitor cell transplantation, respectively. Radiation therapy was administered to all patients that had received breast conserving surgery. Patients received a strong psychological support, biphosphonates, and after the end of chemotherapy, estrogen receptor positive (ER+) patients received an aromatase inhibitor. Results: Characteristics of patients. Median age was 41 years (range, 26-44 yrs). 79% of patients were ER+, while 21% were estrogen receptor negative. Total number of positive nodes was 145, with a mean of 2,7 for each patient (range 0-25). G3 tumors were observed in 33% of patients, C-erB-2 status (FISH) was positive in 17% of patients, while mean Ki-67 value was 27%. Serum estradiol was suppressed to values &amp;lt; 40 pg/mL in all patients. After six months and one year, a statistically significant decrease was observed in T-regs number (p&amp;lt; 0.005) and VEGF (p&amp;lt; 0.005) with respect to baseline values. No impairement of cognitive function was observed with respect to baseline conditions. After a median follow-up of 26 months, 4 years progression-free survival and overall survival rate were 97% and 100%, respectively. Conclusions: These data show that ovarian suppression with a Gn-RH analogue decreases T-regs and VEGF, and seems to improve the expected outcome of PM-HR-BC patients through immunologic mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3722.

Expérience tunisienne dans la prise en charge des lymphomes agressifs de l’adulte : à propos de 337 patients

From January 1997 to December 2005, 337 patients with aggressive non Hodgkin’s lymphoma were treated with one of the two successive multicentric non randomized protocols established in Tunisia. The mean age was 53 years. Most patients had diffuse large cell lymphoma with B phenotype in 86% and T in 14%. The performance status was 2 or 3 in 34% of cases. The LDH were elevated in 74% of cases. Advanced disease (III or IV stage) was noted in 59% of cases and 10% had a tumoral mass greater than 10cm. According to the international prognostic index (IPI) ajusted to age, we distinguish four groups: group 1 (0 factor and age<70 years), group 2 (1-3 factors and age≤60 years), group 3 (1-3 factors and age between 61 and 70 years) and group 4 (1-3 factors and age>70 years). The patients of group 1 (N=47) received 3 courses of CHOP regimen followed by irradiation. The patients of group 2 (N=160) received 4 courses of ACVBP regimen (+ rituximab for 21 patients) followed by consolidation (N=92) or peripheral blood progenitor cell transplantation (N=20). The patients of group 3 (N=61) received 8 courses of CHOP regimen (+ rituximab for 20 patients). The patients of group 4 (N=69) received 6 courses of mini-CEOP regimen (N=48) or 6 courses CVP regimen (N=21). The 4-year overall survival was 56% and the 4-year event free survival was 49%.

Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: a randomised trial

Most allogeneic haematopoietic stem cell transplants now use peripheral blood progenitor cell transplantation (PBPCT) instead of bone-marrow transplantation (BMT). Long-term data on outcome and late effects of PBPCT compared with BMT are scarce. Here we present long-term data from a randomised study comparing PBPCT with BMT. Between February, 1995, and September, 1999, 329 patients with leukaemia received either PBPCT (n=163) or BMT (n=166) from HLA-identical sibling donors after central randomisation accounting for stratification criteria. Follow-up data were collected via questionnaires from 87% (176 of 202; 84 PBPCT, 92 BMT) patients who survived for more than 3 years (median of 9.3 years) after transplantation. Efficacy analyses included all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01020175. 10-year overall survival was 49.1% for patients who underwent PBPCT and 56.5% for patients who underwent BMT (HR 0.83, 95% CI 0.60-1.15; p=0.27). Leukaemia-free survival was 28.3% with BMT versus 13.0% with PBPCT (0.61, CI 0.32-1.16; p=0.12) for acute lymphoblastic leukaemia; 62.3% with BMT versus 47.1% with PBPCT for acute myeloid leukaemia (0.67, 0.39-1.16; p=0.16); and 40.2% with BMT versus 48.5% with PBPCT for chronic myeloid leukaemia (1.12, 0.73-1.74; p=0.60). More patients developed chronic graft-versus-host disease after PBPCT (n=56, 73%) than after BMT (n=46, 56%; p=0.021), with more frequent involvement of skin, liver, and oral mucosa, and more patients who underwent PBPCT needed immunosuppressive treatment 5 years after transplantation (n=20, 26%) than patients who had BMT (n=10, 12%; p=0.024). Nonetheless, there was no difference in performance status, return to work, incidence of bronchiolitis obliterans, and haematopoietic function between the two groups. 14 cases of secondary malignancies occurred (five after BMT, nine after PBPCT), resulting in a cumulative incidence of 3% and 7% after BMT and PBPCT (p=0.17), respectively. More than 9 years after transplantation, overall and leukaemia-free survival remain similar in patients who underwent BMT and PBPCT. Differences in the incidence of chronic graft-versus-host disease and the duration of immunosuppression exist, but do not affect survival, general health status, or late events. No external funding was received.

Immunologic Mechanisms Mediate Benefits of Lutenizing Hormone-Releasing Hormone (LH-RH) in High Risk Premenopausal Breast Cancer Patients (HR-Pre-BC).

Abstract Background: Systematic reviews have found that LH-RH agonists are effective in the treatment of premenopausal women with early breast cancer. In an extended phase II study, 180 premenopausal women with HR-Pre-BC were treated with an LH-RH analogue in order to protect ovaries from the damage of chemotherapy. We hypothesized that the benefits of LH-RH administration could extend, far beyond ovarian protection, to the improvement of immune function and to the decrease of vascular endothelial growth factor (VEGF). In fact estradiol (E2) at physiological doses not only expands T regulatory cells (T-regs) in different tissues but also increases expression of the Foxp3 gene, a hallmark for CD4+CD25+ T-reg cell function, and the interleukin-10 gene as well. In addition, recent studies indicate that E2 modulates VEGF expression in breast cancer cells through transcriptional activation.Methods: From 05-1997 to 05-2007 180 patients with HR-Pre-BC were entered into the study. At baseline, one week before chemotherapy, patients received an LH-RH analogue which was continued for five years. Adjuvant chemotherapy was tailored to the peculiar biologic features of each patient, including cyclophosphamide, methotrexate, and 5-fluorouracil in 24 patients, an anthracycline and taxane based regimens in 156 patients (40 with positive c-erb-2 tumors). Seventeen patients with &amp;gt; 10 positive axillary lymph nodes and 36 patients with triple negative tumors, received a platinum-based consolidation high-dose chemotherapy with or without autologous peripheral blood progenitor cell transplantation, respectively. Radiation therapy was administered to 145 patients. During the 5 years of LH-RH analogue, patients received a strong psychological support, biphosphonates, and after the end of chemotherapy, estrogen receptor positive (ER+) patients received an aromatase inhibitor.Results: Characteristics of patients. The mean patient age was 42 years (range, 26–50 yrs). One hundred-twenty five women were ER+, 55 were estrogen receptor negative (ER-). Total number of positive nodes was 479, with a mean of 2.6 for each patient (range 0-25). UICC stage was II in 114 women and III in 66 women. All patients had their serum E2 suppressed to values &amp;lt; 40 pg/mL. A statistically significant improvement was observed in lymphocyte number (p&amp;lt; 0.005), and a decrease in T-reg number (p&amp;lt; 0.005) and VEGF (p&amp;lt; 0.005) with respect to baseline values, after LH-RH administration. After a median follow-up of 97 months, 10-years overall progression-free survival and overall survival rate were both 83.2% with no statistical significant difference between ER+ and ER- patients.Conclusions: These data show that the administration of an LH-RH analogue improves lymphocyte number, decreases T-regs and VEGF, and seems to improve the expected outcome of HR-Pre-BC patients through immunologic mediated mechanisms. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4092.