Deirdre Duffy

A Phase I Study of Gemtuzumab Ozogamicin (GO) in Combination with Busulfan and Cyclophosphamide (Bu/Cy) and Allogeneic Stem Cell Transplantation in Children with Poor-Risk CD33+ AML: A New Targeted Immunochemotherapy Myeloablative Conditioning (MAC) Regimen

Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day -14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m(2), busulfan on days -7, -6, -5, -4 (12.8-16.0 mg/kg), and cyclophosphamide on days -3 and -2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m(2). No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m(2) in combination with Bu/Cy is currently being tested in a phase II study.

T cell depletion utilizing CD34+ stem cell selection and CD3+ addback from unrelated adult donors in paediatric allogeneic stem cell transplantation recipients

CD34‐selected haploidentical and unrelated donor allogeneic stem cell transplantation (AlloSCT) in paediatric recipients is associated with sustained engraftment and low risk of acute graft‐versus‐host disease (aGVHD), but limited by delayed immune reconstitution and increased risk of viral and fungal infection. The optimal dose of donor T cells to prevent graft failure and minimize risk of early opportunistic infection and post‐transplant lymphoproliferative disorder (PTLD), while avoiding severe aGVHD, remains unknown. We prospectively studied CD34‐selected 8–10/10 human leucocyte antigen (HLA)‐matched unrelated donor (MUD) peripheral blood stem cell transplantation (PBSCT) in a cohort of 19 paediatric AlloSCT recipients with malignant (n = 13) or non‐malignant (n = 6) diseases. T cells were added back to achieve total dose 1·0–2·5 × 105 CD3+/kg. GVHD pharmacoprophylaxis consisted only of tacrolimus. All patients engrafted neutrophils. Probabilities of grade II–IV aGVHD, limited chronic GVHD (cGVHD), and extensive cGVHD were 15·8%, 23·3%, and 0%, respectively. One patient developed PTLD. One‐year infection‐related mortality was 5·6%. T cell immune reconstitution was delayed. One‐year overall survival was 82·3%. Five patients with malignant disease ultimately died from progressive disease. CD34‐selected MUD PBSCT using a defined dose of T cell add‐back resulted in high rates of engraftment and low risk of grade II–IV aGVHD, early transplantation‐related mortality, and extensive cGVHD.

Granulocyte transfusion therapy in pediatric patients after hematopoietic stem cell transplantation: a 5-year single tertiary care center experience.

Background: Granulocyte transfusion (GTx) has been used in neutropenic patients to treat infections; however, there are few studies that document its efficacy, especially in pediatric patients after hematopoietic stem cell transplantation (HSCT). We, therefore, reviewed the use of GTx in these patients. Materials and Methods: A retrospective observational analysis was performed on all pediatric HSCT patients between January 2005 and January 2010 who met our institution’s criteria for GTx and received more than 1 GTx. Unstimulated granulocyte donors were used until June 2007, followed by dexamethasone-stimulated donors thereafter. Outcomes were infection clearance, safety profile of GTx, and 30-day survival. Results: One hundred fifty-three GTxs were administered to 16 pediatric HSCT patients. Indications for GTx: bacterial (69%), fungal (19%), and combined infection (12%). Concurrent infections, mostly bacterial, developed in 60% patients. One adverse reaction (pulmonary toxicity) was reported. The absolute neutrophil count of the stimulated products was significantly higher compared with the unstimulated products; however, neither the average number of granulocytes transfused by weight nor outcomes difference was noticed between these groups. Conclusions: GTx is safe in neutropenic and infected pediatric patients after HSCT. However, no difference in the outcomes was noticed between the group that received stimulated products and the group that received unstimulated products.

Pilot Trial of Risk-Adapted Cyclophosphamide Intensity Based Conditioning and HLA Matched Sibling and Unrelated Cord Blood Stem Cell Transplantation in Newly Diagnosed Pediatric and Adolescent Recipients with Acquired Severe Aplastic Anemia

Cyclophosphamide‐based conditioning regimens and allogeneic hematopoietic stem cell transplantation (AlloHSCT) from matched related donors (MRD) has resulted in the highest survival rates in children and adolescents with acquired severe aplastic anemia (SAA). Time to transplant has consistently been associated with decreased overall survival. Reduced toxicity conditioning and AlloHSCT has been used successfully in other pediatric non‐malignant diseases.