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.     

Delayed short‐term administration of granulocyte colony‐stimulating factor is a good mobilization strategy for harvesting autologous peripheral blood stem cells in pediatric patients with solid tumors

PBSCs have become the preferred source of autologous stem cells for supporting high‐dose chemotherapy in childhood solid tumors. The aims of this retrospective study were to examine the optimal timing for administration of G‐CSF after chemotherapy and to identify the patients from whom an optimal dose of PBSCs can be harvested. We evaluated the timing of G‐CSF administration for harvesting PBSCs in patients with childhood solid tumors. G‐CSF was administered immediately after chemotherapy in eight patients (11 harvests, long‐term group) and following recovery from hematological nadirs in 17 patients (21 harvests, short‐term group). The median duration of G‐CSF administration was 22 vs. 5 days, respectively (p < 0.005), and the dose of harvested CD34⁺ cells (×10⁶/kg) was 1.4 vs. 2.9, respectively (p = 0.023). Our results suggest that short‐term G‐CSF administration is a good strategy for harvesting PBSCs in these patients.     

Sequential administration of sargramostim and filgrastim in pediatric allogeneic stem cell transplantation recipients undergoing myeloablative conditioning

G-CSF and GM-CSF both hasten myeloid engraftment post-MA-alloSCT; however, GM-CSF is earlier acting and less expensive. The objective was to evaluate efficacy/safety of sequential administration of GM-CSF followed by G-CSF in children post-MA-alloSCT. From January 2001 to June 2005, 31 children received 32 MA-alloSCT: mean age 6.65 yr; MRD BM or PBSC vs. related or unrelated UCB 11:21; malignant vs. non-malignant disorders 22:10. GM-CSF (250 microg/m(2) IV QD) began on day of stem cell infusion. GM-CSF was switched to G-CSF (10 microg/kg IV QD) when WBC >or= 300/mm(3) x 2 days. G-CSF continued until ANC >or= 2500/mm(3) x 2 days, then tapered to maintain ANC >or= 1000/mm(3). Median time to myeloid engraftment (ANC >or= 500/mm(3) x 3 days) was 17 days [13 days vs. 24 days, MRD BM/PBSC vs. UCB (p < 0.0001)], occurring at a median time of two days after switch to G-CSF. Clinically relevant adverse events were bone pain (n = 8) and large pleural effusion (n = 1). It was estimated that sequential GM-CSF/G-CSF was cost-effective compared with G-CSF alone [cost-savings of $1311/patient ($41,952/study), 2007 Red Book Average Wholesale Price]. In summary, it was demonstrated that sequential administration of GM-CSF/G-CSF post-MA-alloSCT was safe, cost-effective and resulted in prompt myeloid engraftment.     

Hematopoietic and immune recovery after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation in a pediatric population

To compare the hematopoietic and immune recoveries after allogeneic transplantation with different cell sources, we analyzed the recovery patterns of blood components after allogeneic peripheral blood stem cell transplantation (PBSCT) in comparison with that after allogeneic bone marrow transplantation (BMT) in a pediatric population. Sixteen patients received PBSCT, and 24 received BMT between January, 1995 and March, 2000. The patients had acute lymphoblastic leukemia (ALL; n = 22), acute myelogenous leukemia (AML; n = 8), myelodysplastic syndrome (MDS; n = 3), or other diseases (n = 7). The median ages of patients in the PBSCT and BMT groups were 9 yr and 6 yr, respectively. Cyclosporin A (CsA) plus methotrexate or methylprednisolone was used as a graft-vs.-host disease (GvHD) prophylaxis regimen in the PBSCT group, whereas CsA alone or methotrexate alone was used in the BMT group. Circulating lymphocyte numbers and subpopulations determined by flow cytometric analysis were used as markers of immune recovery. In the PBSCT group, the median number of harvested CD34+ cells was 7.25 (range: 1.3-27.6) x 106/kg of the recipient's body weight, while the median number of harvested nucleated cells was 4.7 (range: 3.7-10.5) x 108/kg. All of the patients were engrafted. Myeloid engraftment occurred sooner after PBSCT than after BMT (median number of days to achieve absolute neutrophil counts (ANC) > 0.5 x 109/L; 11 and 15, respectively; p < 0.0001) and similar results were found for platelet engraftment (median number of days to achieve a platelet count of > 20 x 109/L; 12 and 21, respectively; p = 0.004). On the other hand, after PBSCT the absolute numbers of total circulating lymphocytes and lymphocyte subpopulations were not significantly different from those after BMT. The incidence of acute GvHD after PBSCT was the same as that after BMT, while chronic GvHD developed more frequently after PBSCT than after BMT (p = 0.005). In a pediatric population, the indications for PBSCT and BMT should be based on these findings in addition to regard for the donor's safety.     

Weighing the risks of G-CSF administration, leukopheresis, and standard marrow harvest: ethical and safety considerations for normal pediatric hematopoietic cell donors

BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is used for collection of hematopoietic cells in most adult and a smaller but significant percentage of pediatric normal donor harvests. Short and long-term risks of G-CSF administration and leukopheresis are not well understood in the pediatric population. PROCEDURE: Literature review including observations from the IBMTR, NMDP, EBMT, German Donor Registry, and the authors' work. RESULTS: G-CSF causes temporary discomfort in a minority of younger donors. Rare serious side effects of G-CSF have yet to be reported in children. To date, an increase in hematological malignancies after short-term G-CSF use has not been detected in adult donors and no cases have been reported in children. Reported complications of leukopheresis in children are rare and minor, but donors <20 kg may be exposed to allogeneic blood products. Pediatric aged donors vary widely in their ability to assent or consent to the risks of a donation procedure. There are key regulations and ethical imperitives, which must be addressed in deciding which donation procedures are appropriate for minors. CONCLUSIONS: While short term administration of G-CSF and leukopheresis appear to be safe and effective procedures when used to assist in collection of a hematopoietic cell graft from a normal pediatric donor, institutions adding or substituting one or both of these procedures for standard marrow donation must decide whether the donor should be considered a research subject, and if so, whether the new procedures are a minor increase over minimal risk. Because these procedures are being performed on and off study at many pediatric centers, a comprehensive study addressing donor safety could help clarify risks of rare adverse events.     

Factors associated with bone marrow stem cell yield for pediatric allogeneic stem cell transplantation: The impact of donor characteristics

The aim of this study was to investigate the effects of donor characteristics on CD34⁺ cell yield in BM harvest. Between April 2010 and November 2013, consecutive donors who underwent BM harvesting in our BM transplantation unit were retrospectively investigated. Donors were classified into two groups: those who donated BM without mobilization (steady‐state BM donors) and those who received G‐CSF for stem cell mobilization (G‐CSF‐primed BM donors). Donor characteristics (age, gender, race, body weight, BMI, and laboratory factors including donor's leukocyte, platelet, and monocyte) and their relationship with total nuclear cell and CD34⁺ cell numbers has been evaluated. A total of 64 healthy related donors (29 males/35 females, median age 11.2 years; 49 [76.6%] younger than 18 and 36 [56.3%] younger than 12 years) were included in the study. The median CD34⁺ cell yield in the harvest was 0.12×10⁶/L (0.02‐0.21) in SS‐BM donors and 0.18×10⁶/L (0.09‐0.67) in GP‐BM donors (P=.03). Median of CD34⁺ cell count given to recipients was 2.6×10⁶/recipient body weight (1.3‐19.3) in SS‐BM yields and 3.8×10⁶/recipient body weight (1.1‐10.2) in GP‐BM yields, respectively. Multiple regression analysis showed that donor height and pre‐G‐CSF platelet were the most important parameters to obtain a sufficient BM harvest. Our data suggest that the shorter donors and the donors with higher thrombocyte counts may offer more hematopoietic stem cell. The height and thrombocyte count of the donors should be taken into consideration before planning the targeted CD34⁺ cell count especially for pediatric donors.     

Changes in biomarkers of bone resorption over the first six months after pediatric hematopoietic cell transplantation

Polgreen LE, Rudser K, Deyo M, Smith A, Baker KS, Petryk A. Changes in biomarkers of bone resorption over the first six months after pediatric hematopoietic cell transplantation. Abstract: Bone loss has been observed within the first six months after HCT in both children and adults. While there is some evidence that bone formation may be reduced in children after HCT, it is currently unknown whether bone resorption is increased. The objective of this prospective study was to evaluate changes in markers of bone resorption over the first six months after pediatric HCT. Twenty‐six participants (eight females) aged 10.9 ± 3.4 yr entered the study prior to HCT. Bone resorption was measured by urine DPD and PYD, and by plasma NTX and CTX. Seventeen participants who completed day +30 visit and either day +100 or +180 visits were included in the analysis. DPD increased between days +30 and +100 (mean change, 11.3 nmol/nmol creatinine; p = 0.012) and between days +30 and +180 (13.7 nmol/nmol creatinine; p = 0.036). PYD increased between days +30 and +100 (32 nmBCE/L; p = 0.019). CTX increased between baseline and day +100 (5.9 μg/L; p = 0.012). Changes in NTX levels were not statistically significant. This study shows that markers of bone resorption increase in children after HCT, suggesting that increased resorption may be a contributing factor to the pathophysiology of bone loss after pediatric HCT.     

Childhood blastic NK cell leukemia successfully treated with L-asparagenase and allogeneic bone marrow transplantation

Blastic NK cell lymphoma/leukemia is a rare and highly malignant neoplasia in both adults and children. It is characterized by lymphoblastoid morphology without cytoplasmic granules and immature NK cell immunophenotypes (CD56+, CD57-, CD16-). It has predilection for extranodal organ involvement, and the prognosis of affected patients is extremely poor under the current chemotherapy. We present a 14-year-old girl who was diagnosed as having blastic NK cell leukemia with mediastinal, pleural, and pericardial involvement. Immunophenotyping of her leukemic cells showed positive for CD2, CD5, CD7, CD34, CD56, HLA-DR, and cytoplasmic CD3. T cell receptor (TCR) and Immunoglobulin heavy chain genes were not rearranged. She received chemotherapy for acute lymphoblastic leukemia incorporating L-asparaginase (L-asp) which successfully induced complete remission. Bone marrow transplantation (BMT) from her HLA-identical sibling was conducted after two courses of consolidation therapy. Expression of aspargine synthetase (AS) protein in the leukemic cells at diagnosis was examined by an immunocytochemical method. She remains in hematological remission for over 36 months after BMT. The expression of AS protein was negative, suggesting that the leukemic cells were sensitive to L-asp. Induction and consolidation therapy incorporating L-asp followed by allo-BMT might be a promising treatment for child hood blastic NK cell leukemia, but more samples of the rare leukemia need to be studied before any definitive conclusions can be drawn.     

Therapy‐related Ph+ leukemia after both bone marrow and mesenchymal stem cell transplantation for hypophosphatasia

Bone marrow (BM) transplantation (BMT) is one of the treatment strategies for congenital metabolic disease, but leukemia secondary to intensive cytoreductive treatment is a major concern. Besides BM cells, mesenchymal stem cells (MSC) are also used for transplantation. An 8‐month‐old girl with hypophosphatasia underwent transplantation of haploidentical BM cells followed by two transplants of MSC obtained from her father to facilitate osteogenesis. Fludarabine(Flu)/cyclophosphamide (CPA)/anti‐thymocyte globulin were used for myeloablative conditioning, but the patient developed therapy‐related leukemia harboring t(9;22)(q34;q11.2); minor BCR‐ABL (t‐leukemia with Ph) at the age of 32 months. At the age of 40 months she underwent a second BM and third MSC transplant from the same donor. Thereafter, she achieved complete histological and molecular remission. The present case suggests that the combination of cytotoxic agents (Flu/CPA) and MSC led to t‐leukemia with Ph as a consequence of chromosome instability and suppression of host anti‐tumor immunity.     

Efficacy of high‐dose steroids for bronchiolitis obliterans syndrome post pediatric hematopoietic stem cell transplantation

BOS is the pulmonary manifestation of cGvHD post‐allogeneic HSCT. Survival and treatment of this often fatal complication have not improved over the last 20 years and there is no clear standard of care. For the past 10 years, BOS was treated in our center with monthly cycles of HDPS. We reviewed the outcomes of patients with post‐HSCT BOS who met the diagnostic criteria for BOS as per the NIH consensus and were treated with at least one cycle of methylprednisolone at a dose of 10‐30 mg/kg/d×3 d. We collected demographic and clinical data, responses to treatment and results of pulmonary function tests at several time points. Between January 2007 and January 2014, 12 patients were treated with HDPS for post‐HSCT BOS. Five patients (42%) had a good response to treatment; four patients (33%) stabilized with moderate lung disease; and three patients (25%) progressed to end‐stage disease. No significant acute side effects attributable to the HDPS treatment were identified. HDPS may be an effective treatment option for all but the most severely ill patients with post‐HSCT BOS.     

Cytomegalovirus,adenovirus, and polyomavirus co‐infection among pediatric recipients of allogeneic stem cell transplantation: Characteristics and outcome

Watcharananan SP, Kiertiburanakul S, Piyatuctsanawong W, Anurathapan U, Sungkanuparph S, Pakakasama S, Chantratita W, Hongeng S. Cytomegalovirus, adenovirus, and polyomavirus co‐infection among pediatric recipients of allogeneic stem cell transplantation: Characteristics and outcome.
Pediatr Transplantation 2010: 14:675–681. © 2010 John Wiley & Sons A/S. Abstract: ADV and PMV infection have increasingly been documented as significant complications following allo‐HSCT. Despite increasing recognition, characteristics and outcome of CMV, ADV, and PMV viral co‐infection remain obscured. In this study, a retrospective quantitative PCR analysis of ADV, PMV (BKV and JCV) was performed from pediatric patients’ stored blood samples previously tested for CMV viremia after allo‐HSCT. Clinical and virological characteristics and outcome among patients with and without viral co‐infection were analyzed and compared. From 2001 to 2006, 219 blood samples from 69 patients were studied. Viral DNA was present in 119 samples (52.9%).The proportion of viremia was highest for BKV (30.6%), followed by CMV (20.9%), ADV (9.1%), and JCV (0.5%). Viral co‐infection occurred in 17 patients (24.6%), with CMV/BKV as the most common type (11.6%), followed by CMV/ADV (4.3%) and ADV/BKV (2.9%). From multivariate analysis, factors associated with viral co‐infection were acute GVHD (OR 4.57; 95% CI 1.9–10.96, p = 0.001), level of blood CMV viral load (OR 1.53; 95% CI 1.24–1.89, p < 0.001), and level of blood ADV viral load (OR 1.56; 95% CI 1.05–2.32, p = 0.027). Higher probability of developing viral disease was strongly associated with more types of virus detected in blood (p < 0.001). Significant difference in the causes of death was observed among patients with and without viral co‐infection (p = 0.014). Infection (87.5%) was the major cause of death of patients with viral co‐infection, whereas relapse of hematologic disease (70%) was the major cause of death of patients with mono‐viral infection. Viral co‐infection is a common and significant infectious complication in pediatric recipients of allo‐HSCT. Blood monitoring of CMV, ADV, and BKV is suggested among pediatric patients who develop GvHD or who have rising of CMV or ADV viremia following allo‐HSCT.