Comparison of two cytoreductive regimens for αß-T-cell-depleted haploidentical HSCT in pediatric malignancies: Improved engraftment and outcome with TBI-based regimen.

BACKGROUND: Graft manipulation using selective depletion of αß-T cells provides a source of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) enriched in effector cells. We report our experience implementing this haplo-HSCT for high-risk malignancies in pediatric patients focusing on the conditioning regimen. PROCEDURE: We performed a retrospective study of patients who underwent T-cell receptor αß-depleted haplo-HSCT for high-risk pediatric malignancies. RESULTS: Eighteen patients underwent haplo-HSCT using this method. The initial reduced-toxicity chemotherapy-based conditioning regimen was given to eight patients, and resulted in a high rate of graft rejections (six of eight patients). Thus, total body irradiation (TBI) based regimen was introduced in the following 10 patients and resulted in engraftment in all patients. Neutrophil and platelet engraftment were rapid (median time to engraft, 10 days and 12 days, respectively). Significant treatment-related complications for both cohorts were all due to graft failure in patients receiving chemotherapy-based conditioning, with a treatment-related mortality rate of 17%. None of the patients developed hepatic sinusoidal-obstruction syndrome, and no grade III-IV acute graft versus host disease (GVHD) was observed. The majority of patients were free of immunosuppression in the first 100 days post-HSCT, and only two patients developed chronic GVHD. The cumulative incidence of relapse was 39%. Compared to patients conditioned with chemotherapy, patients conditioned with TBI had superior actuarial overall survival (66% vs. 37%, P = 0.05) and event-free survival (61% vs. 33%, P = 0.04). CONCLUSIONS: A TBI-based conditioning for haplo-HSCT using αß-T-cell depletion for malignant diseases ensured engraftment and resulted in acceptable outcomes.

Spirometry follow-up in young children with hemato-oncologic diseases.

BACKGROUND: Treatment of hemato-oncologic patients is often associated with severe pulmonary complications. Pulmonary function is routinely evaluated in older children, whereas in young patients, forced spirometry measurements are infrequently performed. AIM: To assess severity of airway disease using forced spirometry measured prior to and after treatment (over 3 years) in hemato-oncologic children aged 3-7 years in comparison to a healthy population. MATERIAL/METHODS: 42-children (18-males; age 3-7 years old) with hemato-oncologic illnesses participated in the study. Spirometry was performed before the definitive treatment and up-to 3-years thereafter. Values were compared to those of healthy children of corresponding age. RESULTS: Most children (n=38) showed only minor long term airflow impairment (z-scores of FEV1 at last measurement was -0.00 to -0.45 SD). Prior to definitive treatment eight children presented severe airflow limitation (z-score =-1.35 + or - 0.72; -1.61 + or - 0.66 and -2.49 + or - 0.34 for FEV1, FEV0.5; and FEF25-75 respectively). Four of eight children resumed normal pulmonary function; the spirometry values of the other four children further deteriorated, in association with GVHD and development of bronchiolitis obliterans. CONCLUSIONS: Our study suggests that it is important to follow spirometry in young children with hemato-oncologic diseases in order to detect these patients, whose condition may have prognostic implications for their treatment.

Haploidentical hematopoietic stem cell transplantation with αßTCR+/CD19+ depletion in pediatric patients with malignant and non-malignant disorders.

Haploidntical hematopoietic stem cell transplantation has been increasingly used in recent years for patients without a matched donor. The αßTCR+/CD19+ depletion technique provide a graft that is enriched with CD34 cells, γδ-T-cells and natural killer. The current experience with αßTCR+/CD19+ depleted grafts in pediatric patients with malignant and non-malignant disorders, demonstrated rapid engraftment, improved immune reconstitution and low risk of GVHD. Future studies will need to define the optimal conditioning regimen in order to improve transplant outcome.

Pulmonary function studies in children treated by chemoradiotherapy and stem cell transplantation.

BACKGROUND: Management of pediatric patients with malignant and hematological diseases is frequently associated with pulmonary complications. We assessed pulmonary function at diagnosis and during a 5-year follow-up to identify risk factors associated with pulmonary deterioration. PROCEDURE: Ninety patients (age range 3-20) who were treated at the Pediatric Hematology-Oncology Department, Sheba Medical Center, Israel, were entered into the study. Pulmonary function testing was performed at diagnosis and at least twice during the study period. RESULTS: At diagnosis and thereafter values of spirometry, total lung capacity, functional residual capacity and diffusion capacity were significantly lower than predicted (P < 0.002 for all indices). The ratio between residual volume and total lung capacity (RV/TLC) was significantly higher than normal at diagnosis and throughout the study (P < 0.001). Age and treatment modalities did not show any effect on lung-function during the study. A subgroup of seven patients (8%) developed Bronchiolitis obliterans (BO) after stem cell transplantation and development of graft versus host disease (GVHD). These patients' baseline FEF25-75 values (small airway disease) were significantly lower than FEF25-75 values of controls and other patients while all other parameters were similar. The RV/TLC in the BO patients gradually increased relative to other patients during the 5-year follow-up. CONCLUSION: Lung-function in pediatric hemato-oncological patients at diagnosis is lower than predicted. Abnormal baseline FEF25-75 may be a risk factor for the development of BO in the setting of GVHD after treatment. Careful monitoring, especially of FEF25-75 and RV/TLC at baseline and in the first period after diagnosis.

Nephrectomy in children with wilms' tumor: 15 years of experience with "Tumor Delivery Technique".

BACKGROUND: The contemporary surgical approach to Wilms' tumors follows that used in adults with renal cell carcinomas, namely, early occlusion of the renal vessels and then removal of the kidney as an intact mass. For years, the surgical approach at our institution has been different, starting with blunt separation of the kidney from the surrounding tissues, followed by its delivery outside the abdominal cavity while it is only attached to the major blood vessels which are subsequently ligated. We aimed to present this "tumor delivery technique" and evaluate its outcomes. MATERIALS AND METHODS: We retrospectively reviewed medical records of children who underwent nephrectomy for Wilms' tumor using "tumor delivery technique." All procedures were performed by the same team, according to the same surgical principles. RESULTS: Between 2000 and 2015, 36 children were operated. Median age was 31 months (interquartile range [IQR]: 6-45 mo), and median maximal tumor diameter was 10 cm (IQR: 8-13.9 cm). Tumors were located to the right side in 47%, left side in 42%, and bilateral in 11%. Twelve children have received preoperative neoadjuvant chemotherapy. Capsular disruption and tumor spillage were documented in 4 cases (11%). CONCLUSIONS: "Tumor delivery technique" is an easy and safe approach which might reduce the overall complication rates and the incidence of intraoperative tumor spillage.

Congenital amegakaryocytic thrombocytopenia-3 novel c-MPL mutations and their phenotypic correlations.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare bone marrow failure syndrome associated with thrombocytopenia and a tendency to progress to aplastic anemia. Mutations in the c-MPL gene encoding for thrombopoietin receptor have been identified in the majority of the patients. Previous studies suggest a genotype-phenotype correlation wherein the severity of the disease depends on the type of mutation present and residual thrombopoietin receptor activity. The present study describes the clinical and genetic findings on a series of 7 patients with CAMT, 3 of them siblings. The patients were homozygous for 5 mutations in the c-MPL gene, including 3 unique ones: c.212+5G>A, C76T, and G1162C. The clinical picture was variable; 1 patient who was homozygous for a nonsense mutation in exon 1 (C76T) developed infantile acute lymphoblastic leukemia, whereas patients who were homozygous for a splice-site mutation (c.212+5G>A) expressing both normal and mutated transcripts had a milder clinical course. As previously suggested, c-MPL mutation analysis in CAMT patients helps to predict the clinical course and to provide optimal therapy.