E. Roman

Reduced intensity allogeneic umbilical cord blood transplantation in children and adolescent recipients with malignant and non-malignant diseases.

There is a significant amount of morbidity and mortality following myeloablative umbilical cord blood transplantation (UCBT). Reduced intensity (RI) conditioning offers an alternative to myeloablative conditioning before UCBT. We investigated RI-UCBT in 21 children and adolescents with malignant (n=14), and non-malignant diseases (n=7). RI conditioning consisted of fludarabine (150–180 mg/m2) with either busulfan (⩽8 mg/kg)+rabbit antithymocyte globulin (R-ATG; n=16) or cyclophosphamide+R-ATG±etoposide (n=5). Human leukocyte antigen match: 4/6 (n=13), 5/6 (n=5) and 6/6 (n=3). The median total nucleated cell and CD34+ cell dose per kilogram were 3.58 × 107 and 2.54 × 105, respectively. The median time for neutrophil and platelet engraftment was 17.5 and 52 days, respectively. There were six primary graft failures (chronic myelogenous leukemia (CML), β-thalassemia, hemophagocytic lymphohistiocytosis (HLH) and myelodysplastic syndrome (MDS)). The probability of developing grade II to grade IV acute graft-versus-host disease (GVHD) and chronic GVHD was 28.6 and 16.7%, respectively. Incidence of transplant-related mortality (TRM) was 14%. The 5 years overall survival (OS) in all patients was 59.8%. The 5 years OS for patients with average versus poor-risk malignancy was 77.8 versus 22.2% (P=0.03). RI-UCBT may result in graft failure in specific high-risk chemo-naïve patients (CML, β-thalassemia, HLH and MDS), but in more heavily pretreated pediatric and adolescent recipients results in rapid engraftment and may be associated with decreased severe GVHD and TRM.

Liposomal amphotericin B prophylaxis of invasive mold infections in children post allogeneic stem cell transplantation.

Invasive mold infections (IMI) are a leading cause of infectious mortality in allogeneic stem cell transplant (AlloSCT) recipients. Fluconazole, the current standard for fungal prophylaxis, is ineffective against molds. We initiated a pilot study to determine the safety and activity of prophylactic liposomal amphotericin B (AMB) in preventing IMI in pediatric and adolescent AlloSCT recipients during the first 100 days.

Preliminary Results of the Safety of Immunotherapy with Gemtuzumab Ozogamicin following Reduced Intensity Allogeneic Stem Cell Transplant in Children with CD33+ Acute Myeloid Leukemia

Purpose: Myeloablative allogeneic stem cell transplantation (SCT) has been successful in the treatment of childhood acute myeloid leukemia (AML), but may be associated with significant toxicity and recurrent disease. Reduced-intensity allogeneic SCT may offer a less toxic approach to patients with AML. Targeted immunotherapy with gemtuzumab ozogamicin has been shown to be safe, well tolerated in children, and, as a single agent, gemtuzumab ozogamicin has induced responses in 30% of patients with recurrent CD33+ AML. There are no safety data with gemtuzumab ozogamicin post allogeneic SCT in children. Therefore, we explored the feasibility and toxicity of targeted immunotherapy following reduced-intensity allogeneic SCT in children with CD33+ AML. Experimental Design: Eight patients with CD33+ AML received a reduced-intensity allogeneic SCT following fludarabine 30 mg/m2 for 6 days and busulfan 3.2 mg/kg (<4 years, 4 mg/kg/d) for 2 days. Donor sources included six 6/6 HLA-matched related peripheral blood stem cells, one 6/6 sibling cord blood, and one 4/6 unrelated cord blood. Results: Day 30 and day 60 donor chimerisms in seven of eight evaluable patients were 96 ± 2% (n = 7) and 94 ± 3% (n = 6), respectively. Five of six patients (too early for one patient) received two doses of gemtuzumab ozogamicin and one patient received only one dose. After each dose, all patients developed grade 4 neutropenia, with recovery on median days 16 and 13, respectively, after dose 1 and dose 2. Grade 4 thrombocytopenia was only observed in 2 of 11 gemtuzumab ozogamicin courses. No patients have developed dose-limiting toxicity secondary to gemtuzumab ozogamicin. Conclusions: The administration of gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with average risk AML is feasible and well tolerated with minimal toxicity. The maximal tolerated dose has yet to be determined for gemtuzumab ozogamicin post reduced-intensity allogeneic SCT in children with CD33+ AML. Additional studies in a larger group of patients will be required to adequately assess the safety of this approach.

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

Abstract: 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 μg/m2 IV QD) began on day of stem cell infusion. GM‐CSF was switched to G‐CSF (10 μg/kg IV QD) when WBC ≥ 300/mm3 × 2 days. G‐CSF continued until ANC ≥ 2500/mm3 × 2 days, then tapered to maintain ANC ≥ 1000/mm3. Median time to myeloid engraftment (ANC ≥ 500/mm3 × 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

Immunophenotypic identification of possible therapeutic targets in paediatric non-Hodgkin lymphomas: a children's oncology group report.

1311/patient (

A Low Incidence of Nontuberculous Mycobacterial Infections in Pediatric Hematopoietic Stem Cell Transplantation Recipients

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.

76: Reduced intenity allogeneic stem cell transplantion followed by targeted consolidation immunotherapy with gemtuzumab ozogamicin in children and adolescents with CD33+ acute myeloid leukemia

Immunophenotypic analysis can identify protein epitopes in non‐Hodgkin lymphomas (NHL) that may respond to targeted immunotherapies, such as anti‐CD20 and anti‐CD52. Recent studies suggest additional targets may provide therapeutic benefits in NHL. This study evaluated protein expression of CD25, CD52, CD74 and CD80 in paediatric NHL to determine possible targets for immune‐based therapeutic approaches. Patient samples were derived from paediatric NHL clinical trials sponsored by the Childrens Cancer Group (CCG, now the Childrens Oncology Group, COG) and included Burkitt lymphoma (BL), diffuse large B‐cell lymphoma (DLBCL), disseminated T‐ and B‐cell lymphoblastic lymphoma (T‐LBL and B‐LBL) and anaplastic large cell (ALCL). Immunophenotypic studies were performed on formalin‐fixed, paraffin‐embedded diagnostic tissues. CD25 was expressed in 8% of T‐LBL and 75% of ALCL cases, but not in BL, DLBCL, or B‐LBL. CD52 was expressed in 99% of cases of paediatric NHL of all subtypes. CD74 was expressed in 100% of B‐LBL, BL and DLBCL, but was absent in ALCL and T‐LBL. CD80 was expressed in 12% of B‐LBL, 6% of BL and 10% of DLBCL cases studied, but was not detected in T‐cell NHL. These expression patterns suggest that CD25, CD52 and CD74 may represent potential new therapeutic targets in paediatric NHL.