Pediatric Blood And Marrow Transplant Consortium Research Articles

Elevated ADA2 Enzyme Activity at the Onset of Chronic Graft-versus-Host Disease in Children

Adenosinergic signaling has potent, context-specific effects on immune cells, particularly on the dysregulation of lymphocytes. This in turn may have a role in immune activation and loss of tolerance in such diseases as chronic graft-versus-host disease (chronic GVHD). We assessed whether changes in the enzymatic activity of adenosine deaminase 2 (ADA2), an enzyme that depletes adenosine in the extracellular space via conversion to inosine, may be associated with the onset of chronic GVHD. ADA2-specific enzyme activity was measured in plasma samples from 230 pediatric hematopoietic stem cell transplantation (HSCT) recipients enrolled on the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) 1202 study and compared between patients developing chronic GVHD and those not developing chronic GVHD within 12 months of transplantation. ADA2 and its relationships with 219 previously measured plasma-soluble proteins, metabolites, and immune cell populations were evaluated as well. Plasma ADA2 enzyme activity was significantly elevated in pediatric HSCT recipients at the onset of chronic GVHD compared to patients without chronic GVHD and was not associated with prior history of acute GVHD or generalized inflammation as measured by C-reactive protein concentration. ADA2-specific enzyme activity met our criteria as a potential diagnostic biomarker of chronic GVHD (effect ratio ≥1.30 or ≤.75; area under the receiver operating characteristic curve ≥.60; P < .05) and was positively associated with markers of immune activation previously identified in pediatric chronic GVHD patients. These results support the potential of ADA2 enzyme activity, in combination with other biomarkers and subject to future validation, to aid the diagnosis of chronic GVHD in children post-HSCT.

Haploidentical BMT Using Fully Myeloablative Conditioning, T Cell Replete Bone Marrow Grafts, and Post-Transplant Cyclophosphamide (PT/Cy) Has Limited Toxicity and Promising Efficacy in the First Prospective Multicenter Trial for Pediatric, Adolescent, and Young Adult Patients with High Risk Acute Leukemias and Myelodysplastic Syndrome

Promising results have been reported for patients with high-risk hematologic malignancies undergoing T-cell-replete myeloablative bone marrow transplant (BMT) from HLA-haploidentical donors with post-transplantation cyclophosphamide (PT/Cy). Here, we report results from the first prospective multicenter pilot trial in the Pediatric Blood and Marrow Transplant Consortium (PBMTC) for pediatric, adolescent, and young adult patients with high risk acute leukemias and myelodysplastic syndrome (MDS) in the US and Canada. Nine centers transplanted 32 patients with acute leukemias or MDS in complete remission (CR) who received myeloablative conditioning consisting of IV Busulfan (pharmacokinetically adjusted) and Cyclophosphamide (Cy, 50 mg/kg/day) days –2 and –1 except for patients with acute lymphocytic leukemia who received Cy (50 mg/kg/day x 2) and total body irradiation (1200cGy). T-cell-replete bone marrow from haploidentical related donors was used for all patients. Postgrafting immunosuppression consisted of Cy (50 mg/kg/day) days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 90-180 days. Median age of patients was 12y (range, 1-23) and donors was 35y (range, 4-53). Diagnoses included AML (CR1 = 7, CR2 = 6), ALL (CR1 = 8, CR2 = 5), mixed lineage leukemia (1), and MDS (5). One patient had received a prior BMT. Donor engraftment occurred in 27/32 (84%). Primary graft failures included 3 patients with MDS and 2 with AML (CR1 = 1, CR2 = 1); three of these patients had received suboptimal bone marrow grafts (TNC/kg ≤2e8) and all successfully engrafted after second transplants. Median time to neutrophils >500/μL was 22 days and platelets >20,000/μL was 21 days. Transplant related mortality (TRM) at 180 days, our primary objective, was 0%. Cumulative incidence of acute GVHD grades II-IV at Day 100 was 13%. No patients developed severe acute GVHD grades III-IV. The cumulative incidence of mod-severe chronic GVHD at 1 year was 4%. The cumulative incidence of relapse at 1y was 32%. With a median follow-up of surviving patients of 477 days (range, 180-1127), actuarial overall survival is 77% at 1y. With a median follow-up of event-free patients of 451 days (180-1127), actuarial event-free survival is 68% at 1y. For this first reported multicenter pediatric myeloablative HLA-haploidentical HSCT for high-risk leukemias and MDS with T-cell replete bone marrow and PT/Cy, we have demonstrated a 0% TRM, low cumulative incidences of acute and chronic GVHD, and favorable rates of relapse and survival. Further investigation as to potential reasons for graft failure and consideration of any changes needed to ensure engraftment for certain disease groups are underway. A larger trial comparing haploidentical BMT with other alternative donor sources is in development.

57 - Challenges with Diagnosing Pulmonary Chronic GVHD in Children as Per the 2014 National Institutes of Health Consensus Criteria: Applied Biomarkers of Late Effects (ABLE)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) 1202 Study

57 - Challenges with Diagnosing Pulmonary Chronic GVHD in Children as Per the 2014 National Institutes of Health Consensus Criteria: Applied Biomarkers of Late Effects (ABLE)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) 1202 Study

Multicenter Investigation Of Unrelated Donor Hematopoietic Cell Transplantation (HCT) For Thalassemia Major After a Reduced Intensity Conditioning Regimen (URTH Trial)

BackgroundHCT cures thalassemia major (TM). In the absence of a family donor, marrow or less frequently umbilical cord blood (UCB) from unrelated donors (URD) has been used. Due to risks of graft rejection, myeloablative preparative regimens are primarily utilized. URD marrow and UCB HCT have 65-90% and 21-74% event free survival (EFS) and rejection rates of 9-17% and 17-57% respectively.The URTH trial was developed in collaboration with the Thalassemia Clinical Research Network (TCRN), National Heart, Lung and Blood Institute (NHLBI), Pediatric Blood and Marrow Transplant Consortium (PBMTC) and New England Research Institutes (NERI) to explore URD HCT for TM as a strategy to expand availability of HCT. It employed reduced intensity conditioning (RIC) as a means to decrease early and late toxicities. The study tested our hypothesis that an immunosuppressive RIC regimen was sufficient for engraftment in children with TM (age > 1 year to < 17 years) after URD HCT. The primary objective was to determine EFS at 1 year after URD marrow or UCB HCT. MethodsPatients with transfusion dependent beta thalassemia and a suitable URD (matched at 8/8 HLA-alleles in marrow donors or 5 to 6/6 HLA antigens in UCB donors) were conditioned with hydroxyurea (30mg/kg x 30 days) (day -50 to -21), alemtuzumab (48 mg) (-22 to -19), fludarabine (150 mg/m2) (-8 to -4), thiotepa (8mg/kg) (-4), and melphalan (140mg/m2) (-3). Patients received tacrolimus or cyclosporine with methotrexate and methylprednisone (marrow) or mycophenolate mofetil (UCB) after HCT to prevent graft-versus-host disease (GVHD). Suitable UCB units were defined as having a pre-thaw total nucleated cell content >4.0x10E7/Kg recipient weight. Patients were eligible irrespective of Pesaro classification but the presence of liver fibrosis by histology was an exclusion criterion. ResultsTwenty-three patients from 11 US centers (11M: 12F) with a median age of 10 years (2–17 years) received unrelated donor allografts: marrow (14) or UCB matched at 6/6 (1) or 5/6 HLA antigens (8). The median follow up time was 12 months (range 120 days-2 years). The median time to neutrophil engraftment was 13 days (range 10-25) and 34 days (range 12-46) after marrow and UCB HCT respectively. The median time to platelet engraftment after marrow and UCB HCT was 24 days (range 18-34) and 54.5 days (range 32-234) respectively. Primary graft rejection occurred in 1 patient (4% of all patients) following UCB HCT and was accompanied by autologous hematopoietic recovery 35 days after HCT. All others had >90% donor chimerism and achieved transfusion independence. There were no late graft rejections. The overall and EFS probabilities were 82% and 78% respectively at the most recent encounter.One patient developed mild VOD which resolved uneventfully. Of 15 patients who had CMV reactivation, 13 responded to pre-emptive therapy and had no progression to CMV disease. The probabilities of grade II-IV and grade III-IV acute GVHD were 30% and 9% respectively. Limited chronic GVHD was noted in 35% of the cohort; 9% developed extensive cGVHD. Four patients died on days 25, 86, 106 and 366. The causes of death included 1) pulmonary hemorrhage associated with CMV, adenovirus, and Pneumocystis jiroveci infections, 2) diffuse alveolar pulmonary hemorrhage, 3) cGVHD with pneumonia associated with CMV and adenovirus infections, and 4) cGVHD with pulmonary failure associated with CMV and EBV infections and presumed central nervous system post-transplantation lymphoproliferative disease. ConclusionHCT after RIC for thalassemia is feasible and sufficient for engraftment after URD marrow and UCB transplantation with survival exceeding 80%. The principal transplant- related complications we observed were early opportunistic viral reactivations; otherwise the preparative regimen was tolerated well with very little early toxicity. Fatal and late viral infections were noted only in the setting of severe GVHD. Patients should be monitored carefully and treated promptly for infectious complications after HCT until there is adequate immune reconstitution. The risk of severe GVHD was low despite unrelated and mismatched (UCB) donor sources. Longer follow up will determine if this regimen can reduce late toxicities. An extension of this trial is ongoing and currently recruiting patients to evaluate additional HCT related and quality of life measures. Disclosures:Neufeld:Shire: Consultancy. Kwiatkowski:Resonance Health: Research Funding; Shire: Consultancy. Thompson:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Honoraria; Glaxo Smith Kline: Research Funding; Eli Lilly: Research Funding; Amgen: Research Funding; bluebird bio: Research Funding.

Competitive TNF Inhibitor (ETANERCEPT) for the Treatment of Idiopathic Pneumonia Syndrome (IPS) Following Allogeneic Stem Cell Transplantation (SCT). A Joint Pediatric Blood and Marrow Transplant Consortium (PBMTC) and Childrens Oncology Group (COG) Study

Competitive TNF Inhibitor (ETANERCEPT) for the Treatment of Idiopathic Pneumonia Syndrome (IPS) Following Allogeneic Stem Cell Transplantation (SCT). A Joint Pediatric Blood and Marrow Transplant Consortium (PBMTC) and Childrens Oncology Group (COG) Study

Relationship between pediatric blood and marrow transplant center volume and day +100 mortality: Pediatric Blood and Marrow Transplant Consortium experience

The number of patients receiving a BMT is currently being used as a factor in the accreditation process in determining whether a center can provide a high-quality BMT. Such criteria particularly impact pediatric BMT centers as most of them perform a relatively small number of BMTs. To determine whether patient volume is a valid marker of pediatric BMT center's capabilities, the Pediatric Blood and Marrow Transplant Consortium (PBMTC) evaluated data from its registry to define the relationship between a pediatric transplant center's patient volume and day +100 mortality. The analyses evaluated 2575 transplants from 60 centers reporting to the PBMTC between the years 2002 and 2004. The volume-outcome relationship was evaluated while adjusting for 46 independent data categories divided between nine variables that were known- or suspected-mortality risk factors. We found no association between transplant center volume and day +100 mortality in several analyses. A calculated intraclass correlation coefficient also indicated that differences in individual transplant center volume contributed to only 1% of the variance in day +100 mortality within the PBMTC. The results of this study suggest that factors other than transplant center volume contribute to variation in day +100 mortality among pediatric patients.

The management of menstrual suppression and uterine bleeding: A survey of current practices in the pediatric blood and marrow transplant consortium

Current guidelines recommend the use of combined hormonal contraceptive pills for menstrual suppression in pediatric blood and marrow transplant (BMT) recipients but recent research reveals that provider practice varies. This study was designed to describe the current practice for managing menstrual issues, that is, menstrual suppression and uterine bleeding, in pediatric BMT patients and to better understand health care providers' practices in the use of gonadotropin-releasing hormone agonists (GnRHa). A cross sectional survey consisting of 53 questions was distributed via email to principal investigators in the Pediatric Blood and Marrow Transplant Consortium (PBMTC). Responses were collected using www.surveymonkey.com. Menstrual suppression and uterine bleeding in pediatric BMT patients are primarily managed by pediatric oncologists (97%). The most frequently reported hormonal method used for induction of therapeutic amenorrhea was GnRHa (41%). The top three reasons for choosing a method were greater likelihood of amenorrhea, concerns about side effects, and possible gonadal protection. Continuous combined hormonal contraceptive pills were the most commonly used method for the management of clinically significant uterine bleeding regardless of primary method used for menstrual suppression. Despite the 2002 PBMTC guidelines, wide variation in menstrual suppression management practices still exists. Our data show that use of GnRHa is more common than previously reported. Additional research is needed to develop evidence-based practice guidelines in pediatric BMT patients.

Post‐hematopoietic stem cell transplant immunization practices in the Pediatric Blood and Marrow Transplant Consortium

A survey of National Marrow Donor Program transplant centers in 1995 demonstrated a wide range of immunization practices in post-hematopoietic stem cell transplant (HSCT) recipients, which led to the 2000 Centers for Disease Control and Prevention (CDC) recommendations for vaccination after HSCT. We surveyed the principal investigators of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) to identify immunization practice patterns after HSCT and assess compliance with the 2000 CDC guidelines. Approval was obtained from the Medical University of South Carolina Institutional Review Board. A 33 question survey using surveymonkey.com was distributed by email to principal investigators in the PBMTC. Forty-one (40%) of the 102 pediatric HSCT centers participating in the PBMTC responded. Thirty of the responding centers completed the entire survey. For individual vaccines, compliance with the CDC guidelines ranged from 22% to 93%. Less than 20% of the centers reported schedules consistent with the 2000 CDC recommendations for both allogeneic and autologous HSCT recipients. Despite the 2000 CDC guidelines, wide variation in post-HSCT immunization practices still exists. Updated guidelines have been needed, particularly to address the use of the pneumococcal conjugate vaccine. In conjunction with multiple other groups, the CDC recently released new immunization guidelines in October 2009. Additional data are still needed to adequately address the utility of incorporating immunologic parameters with the timing of vaccination after HSCT.

Impact of Conditioning Regimen in Allogeneic Hematopoetic Stem Cell Transplantation for Children with Acute Myelogenous Leukemia beyond First Complete Remission: A Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study

Total body irradiation (TBI)-based conditioning regimens for pediatric patients with acute myelogenous leukemia (AML) beyond first complete remission (CR1) are controversial. Because the long-term morbidity of busulfan (Bu)-based regimens appears to be lower, determining efficacy is critical. We retrospectively evaluated 151 pediatric patients with AML beyond CR1, comparing outcomes in 90 patients who received a TBI-based conditioning regimen and 61 patients who received a Bu-based conditioning regimen. There were no differences between the 2 groups with respect to age, sex, duration of CR1, time from most recent remission to transplantation, or donor source. The probability of relapse at 2 years also did not differ between the 2 groups (26% and 27%, respectively; P=.93). No significant difference in event-free survival (EFS) (P=.29) or overall survival (OS) (P=.11) was noted between the 2 groups. These findings were supported by a multivariate analysis in which TBI was not associated with improved EFS (hazard ratio [HR]=1.17; 95% confidence interval [CI]=0.66-2.10; P=.58) or OS (HR=1.42; 95% CI=0.76-2.64; P=.27). Shorter CR1 and receiving an HLA-mismatched transplant adversely affected EFS and OS in this cohort. Our study provides no evidence of an advantage to using TBI in children with AML beyond CR1. A prospective, randomized study is needed to confirm these results.

Impact of Conditioning Regimen in Allogeneic Hematopoetic Stem Cell Tansplant for Children with AML beyond the First Complete Remission: Total Body Irradiation Versus Busulfan- a Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study

Busulfan (Bu) based preparative regimen is the most commonly used regimen for children with AML in 1st complete remission (CR). However conditioning regimens for children with AML beyond the first clinical remission (≥ 2nd CR) often include total body irradiation (TBI), which may result in significant long term sequelae. There are limited data concerning outcome in children with AML beyond 1st CR and no data comparing conditioning regimens in this population. One hundred fifty-one patients ≤ 21 years with AML in ≥ CR2 were included in this study. These patients were treated at 47 pediatric transplant centers between 2000 and 2007 with complete data forms reported to the PBMTC database. The median follow up was 2.6 years (range 0.25–8.02). One hundred thirty-four (92%) were in CR2 with a median age 9.2 years (range 0.8–21.6). Ninety (60%) received TBI based regimens and 61 (40%) received Bu based regimens. A majority of those patients received TBI or Bu in combination with cyclophosphamide. Twenty-six (17%) received related donor transplants and 125 (83%) received stem cells from unrelated sources. Thirty nine percent of patients received cord blood transplants. AML was considered high risk in 4 (3%) patients, intermediate risk in 98 (82%) and low risk in 17 (14%). The median time between CR1 and relapse was 12 months (range 1–60) and from achieving 2nd CR to transplant was 1.5 months (range 0.23–10.4). There were no significant differences between patients receiving TBI and Bu conditioning regimens with respect to age, sex, disease risk, pretransplant performance score, duration of CR1, time from CR2 to transplant and stem cell or donor source. There were significantly more patients with history of extramedullary disease in the TBI group (36% vs. 18%, p=0.02). Transplant related mortality (TRM) was not significantly different between the TBI and Bu groups (22% vs. 16%, p=0.29). Infection was the most common cause of death accounting for 39 % of the overall TRM. The probability of relapse at 2 years was 26% and 27% in the TBI and Bu groups, respectively, and it was not significantly different (p=0.93). The probability of progression free survival (PFS) and overall survival (OS) at 2 years was 55% and 56 % respectively. There was no difference in PFS (p=0.29) or OS (p=0.11) between the 2 groups. A multivariable analysis was performed including patients age, donor relation (related versus unrelated), presence of extramedullary disease, donor sex, duration of CR1, time from CR2 to transplant, presence of HLA mismatch and use of TBI. Longer duration of CR1 was associated with improved OS (HR=0.93, 0.90 – 0.97, p<0.001) and PFS (HR=0.94, 0.91 – 0.97, p<0.001). Longer time from CR2 to transplant decreased OS (HR=1.28, 1.07 – 1.53, p=0.007) and PFS (HR=1.21, 1.02 – 1.44, p=0.033). Receiving a transplant from HLA mismatched donor decreased OS (HR=2.04, 1.07 – 3.86, p=0.030) and PFS (HR=2.04, 1.10 – 3.77, p=0.024). The use of TBI was not associated with improved PFS (HR=1.18, 0.66–2.11, p=0.58) or OS (HR=1.42, 0.77–2.65, p=0.27). Shorter duration of first complete remission, longer time from second remission to transplant and receiving HLA mismatched allogeneic transplant adversely affected PFS and OS. Our study provided no evidence of an advantage to using TBI in children with AML beyond first complete remission.

61: Multi-Institutional Phase II Study of Pentostatin for the Treatment of Refractory Chronic GVHD (cGVHD) in Children: A Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study

61: Multi-Institutional Phase II Study of Pentostatin for the Treatment of Refractory Chronic GVHD (cGVHD) in Children: A Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study

A prospective study of G-CSF–primed bone marrow as a stem-cell source for allogeneic bone marrow transplantation in children: a Pediatric Blood and Marrow Transplant Consortium (PBMTC) study

A prospective multicenter trial was conducted to evaluate the safety and feasibility of granulocyte colony-stimulating factor (G-CSF)-primed bone marrow (G-BM) in children receiving allogeneic bone marrow transplantation (BMT). A total of 42 children with a median age of 9.8 years (range, 0.8-17 years) were enrolled. Donors with median age of 9.2 years (range, 1.1-22 years) received 5 microg/kg per day of subcutaneous G-CSF for 5 consecutive days. BM was harvested on the fifth day. No donor experienced complications related to G-CSF administration or marrow har-vest. Median nucleated (NC) and CD34 cells infused was 6.7 x 10(8)/kg (range, 2.4-18.5 x 10(8)/kg) and 7.4 x 10(6)/kg (range, 2-27.6 x 10(6)/kg), respectively. Neutrophil and platelet engraftment was at a median of 19 days (range, 13-28 days) and 20 days (range, 9-44 days), respectively. A total of 13 (32%) patients developed grade 2 graft-versus-host disease (GVHD), and 5 (13%) of 40 evaluable patients developed chronic GVHD (3 limited and 2 extensive). Higher cell dose was not associated with increased risk of acute or chronic GVHD. Overall survival and event-free survival at 2 years were 81% and 69%, respectively. Collection of G-BM from pediatric donors is safe, and can result in high NC and CD34 cell doses that facilitate engraftment after myeloablative BMT without a discernable increase in the risk of GVHD.

Successful Engraftment Using Varied Stem Cell Sources, Low Toxicity, and Long-Term Survival Using a Bu/Flu/ATG Reduced Intensity Allogeneic Transplantation in High Risk Pediatric Patients Ineligible for Myelablative Therapy: Results of the Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study ONC0313.

The role of reduced intensity conditioning (RIC) regimens in pediatric pts is unclear. To define the feasibility and toxicity of a bu/flu/ATG approach in pediatric pts ineligible for myeloablative transplant, we completed a trial at 25 North American and Australian institutions participating in the PBMTC. Forty six pediatric pts (age 2–20yrs, med 11) were enrolled with the following stem cell sources: 8 related donor (RD) BM (2 mismatched); 8 RD-PBSC; 10 unrelated donor (UD) BM; 8 UD-PBSC; 12 UD-CB. Qualifying indications included a previous allogeneic (n=22) or autologous (n=7) transplant, severe organ toxicity (n=8), invasive fungal infection (n=3), and other comorbidities (n= 6 pts, 4 with Down syndrome). Diagnoses included ALL (4 CR2; 11 CR3, 1 secondary), AML (7 CR2; 3 CR3; 3 secondary, 2 PR2+), MLL (1 CR3), CML (1 CR3), HD (3 CR3, 1 PR3), B-NHL (1 PR3), MDS (1 RA; 6 secondary), and JMML (1 PR2, 1 PR3). Patients received busulfan 0.8mg/kg/dose IV x 8 doses (target AUC 900–1100 uM/min), fludarabine 30mg/m2/d x 6 days, and thymoglobulin, 2.5 mg/m2/d x 1 day for RD and x 4 days for UD and UCB. GVHD prophylaxis consisted of cyclosporine (CSP) and mycophenylate mofetil (MMF, 15mg/kg bid). MMF was stopped at day +30 for RD and CB recipients and tapered between d +40–100 for UD recipients. CSP was tapered between d+42–100 for RD and d+100–180 for UD and UCB. Four pts rejected their grafts (9%), one after mismatched RD-BM, two after UD-BM and one after UCB. Two pts died prior to day 100 due to toxicity (4%) and the overall NRM was 11%. Acute GVHD occurred in 9/33 evaluable patients (grade I 9%, grade II 18%, no grade III-IV) and chronic GVHD occurred in 7/28 (25%) evaluable pts. Median follow up is 17 months (range 1–45 m). Two year EFS (events: rejection, relapse, death in remission) is 38% (SE 8) and 2yr OS is 51% (SE 9). No difference in outcome was noted based upon stem cell source, history of previous BMT vs. none, or ALL vs. myeloid disease vs. lymphoma. A trend toward improved survival was noted in “intermediate risk” patients (ALL CR2, AML CR2, and primary MDS without h/o previous BMT: 2yr OS 67 vs. 31%, intermediate vs. high risk, p=0.1). Patients who had undergone transplantation trended toward better survival when their previous myeloablative regimen did not contain TBI (2yr OS 82 vs. 31%, non-TBI vs. TBI, p=0.09). In conclusion, RIC using bu/flu/ATG in a cooperative group setting leads to engraftment in >90% of high risk pediatric pts using related or unrelated BM or PBSC, or unrelated CB. In spite of significant prior therapy, high risk disease, and a high rate of comorbidities in this cohort, the risk of NRM or GVHD is low. Prolonged survival has occurred not only in pts with myeloid disease (2yr OS 43% (SE 12)), but also in pts with ALL (2yr OS 49% (SE 15)), and lymphoma (2yr OS 50% (SE 35)). Flu/bu/ATG is a promising approach for pediatric pts ineligible for myeloablative transplant.

Use of G‐CSF in Matched Sibling Donor Pediatric Allogeneic Transplantation: A Consensus Statement from the Children's Oncology Group (COG) Transplant Discipline Committee and Pediatric Blood and Marrow Transplant Consortium (PBMTC) Executive Committee

Preliminary studies indicate that G-CSF-primed marrow harvesting may result in a graft with increased mononuclear cells collected, increased CD34(+) stem and progenitor cell dose and a potential for more rapid engraftment. Increased cell dose plus other potential positive effects of G-CSF priming have resulted in improved survival in non-randomized preliminary studies. These benefits may be available without the increased risk of chronic graft versus host disease (GVHD) that is experienced with allogeneic peripheral blood stem cell (PBSC) transplant. A phase III Children's Oncology Group (COG)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) trial comparing G-CSF-primed marrow to standard marrow has been proposed. This document reviews background studies of G-CSF-primed marrow and addresses benefits and risks of G-CSF administration to normal pediatric donors. We conclude that the approach is promising and warrants further study. Risks of G-CSF to the donor are minimal and benefits to both donor and recipient may occur.

A Prospective Study of G-CSF Primed Bone Marrow from Pediatric Donors as a Stem Cell Source for Allogeneic Bone Marrow Transplant: A Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study.

Higher bone marrow cell dose has been associated with improved survival after allogeneic BMT. Although PBSC provides higher cell dose, it also provides a higher number of T cells which increases the risk of GVHD and may negatively impact the outcome in pediatric patients. A prospective multi-center trial was conducted to evaluate the safety and feasibility of G-CSF primed bone marrow in children receiving HLA-identical sibling bone marrow transplantation (BMT). Thirty eight children at 9 different centers, 17 female and 21 male with a median age of 9.8 years (range 0.8–17) were enrolled between May 2003 and May 2005. Fifteen patients had high risk diseases (ALL ≥CR2=4, AML≥ CR2/refractory=5, Advanced MDS=3, JMML=1, NHL=2) and 23 had standard risk disease (SAA=6, Red Cell Aplasia=1, Sickle cell disease=1, CML-CP=2, AML CR1=9, ALL CR1=2, MDS-RA=2). Five patients had undergone a prior allogeneic transplant. All patients received myeloablative preparative regimens (Cy/TBI±VP-16=12, BU/Cy±other=20 and Cy/ATG=6) and 32 (84%) received CSP/FK506 with MTX as GVHD prophylaxis. Donors were HLA identical siblings except for one who was syngeneic. Donors with median age of 9.2 y (range 1.1–22) received 5 mcg/kg/day of GCSF SQ for 5 consecutive days. Bone marrow was collected on the fifth day with a median volume of 14.5 cc/kg (range 5.2–25). No donor experienced any complications related to G-CSF administration or harvest, up to the time of last follow-up at one month after the harvest. The absolute CD34 cell count at the day of the harvest was measured in 28 patients and it was significantly higher in bone marrow compared to peripheral blood, median of 50/μl (8–247) vs 513/μl (116–156) respectively (p <0.0001). Median nucleated and CD 34 cells infused was 8.4x108/kg (range 2.4–60.9) and 8.7x106/kg (range 2–27.6) respectively. No G-CSF was administered post transplant. All patients had neutrophil engraftment at a median of 19 days (13–28), and all but one patient with early post-transplant relapse had platelet engraftment at a median of 20 days (9–44). Thirteen patients (35%) developed grade 2 GVHD and 4 of 34 evaluable patients (12%) developed chronic GVHD (3 limited and 1 extensive). There was no transplant related mortality. Among 30 patients with malignant disorders 9 (30%) relapsed (6 with high risk and 3 with standard risk disease). The EFS and OS of patients with standard disease at 1 year is 84% (95% CI 68–100%) and 95% (95% CI 87–100) respectively. With a median follow up of 1 year the estimated EFS and OS of all patients at one year is 76% (CI 62–93) and 92% (95% CI 83–100) respectively. We conclude that G-CSF primed bone marrow from pediatric donors is safe and can result in high NC and CD34 cell dose that facilitate engraftment after myeloablative BMT without a discernable increase in the risk of GVHD. A prospective randomized trial comparing G-CSF primed bone marrow to unstimulated marrow is planned.