Mediport use as an acceptable standard for CAR T cell infusion.

Introduction: Mediport use as a clinical option for the administration of chimeric antigen receptor T cell (CAR T cell) therapy in patients with B-cell malignancies has yet to be standardized. Concern for mediport dislodgement, cell infiltration, and ineffective therapy delivery to systemic circulation has resulted in variable practice with intravenous administration of CAR T cell therapy. With CAR T cell commercialization, it is important to establish practice standards for CAR T cell delivery. We conducted a study to establish usage patterns of mediports in the clinical setting and provide a standard of care recommendation for mediport use as an acceptable form of access for CAR T cell infusions. Methods: In this retrospective cohort study, data on mediport use and infiltration rate was collected from a survey across 34 medical centers in the Pediatric Real-World CAR Consortium, capturing 504 CAR T cell infusion routes across 489 patients. Data represents the largest, and to our knowledge sole, report on clinical CAR T cell infusion practice patterns since FDA approval and CAR T cell commercialization in 2017. Results: Across 34 sites, all reported tunneled central venous catheters, including Broviac® and Hickman® catheters, as accepted standard venous options for CAR T cell infusion. Use of mediports as a standard clinical practice was reported in 29 of 34 sites (85%). Of 489 evaluable patients with reported route of CAR T cell infusion, 184 patients were infused using mediports, with no reported incidences of CAR T cell infiltration. Discussion/Conclusion: Based on current clinical practice, mediports are a commonly utilized form of access for CAR T cell therapy administration. These findings support the safe practice of mediport usage as an accepted standard line option for CAR T cell infusion.

Mixed donor chimerism following stem cell transplantation for sickle cell disease.

Sickle cell disease is a debilitating hemoglobinopathy with high morbidity and mortality. Hematopoietic stem cell transplantation (HCT) is curative, but the presence of mixed donor/recipient chimerism post-HCT raises concerns about disease control long-term. Mixed donor/recipient chimerism is reported in significant numbers even after aggressive HCT conditioning regimens. Post-HCT, adequacy of donor erythropoiesis is crucial for disease control. This review explores the relationship between mixed donor/recipient chimerism and outcomes post-HCT. Serial chimerism analysis in lineage specific manner in erythroid or myeloid cells post-HCT predicts for disease control and HCT success. Adequate and stable donor-derived erythropoiesis is essential for reversing SCD manifestations. Myeloid lineage chimerism mirrors erythropoiesis is commercially available, and a reliable indicator of adequacy. Using this tool, the minimum threshold of donor chimerism is required to prevent SCD-related complications and maintain sickle hemoglobin less than 50% is approximately 20-25% even when a donor has Hb S trait. Curative interventions should, at a minimum, meet this goal long-term. Achieving a balance between successful engraftment while minimizing toxicity is important in patients vulnerable because of age or preexisting morbidity and is the objective of recent clinical trials. As HCT and gene therapies evolve, efficient long-term follow-up that includes durability assessment of mixed donor/recipient chimerism will be crucial.

Granulocyte Colony-Stimulating Factor Is Safe and Well Tolerated following Allogeneic Transplantation in Patients with Sickle Cell Disease.

Granulocyte colony-stimulating factor (G-CSF) used after hematopoietic stem cell transplantation (HSCT) can enhance neutrophil recovery in patients rendered neutropenic by the preparative regimen. G-CSF is contraindicated in patients with sickle cell disease (SCD), because life-threatening complications can ensue in the presence of sickle vasculopathy. The safety profile of G-CSF after HSCT for SCD has not been described, however. We report clinical outcomes in the first 100 days post-HSCT in 62 patients supported with G-CSF until neutrophil recovery on a clinical trial of reduced- intensity conditioning HSCT for SCD. The patients received G-CSF for a median of 9 days (range, 5 to 33 days) post-transplantation from the best available stem cell source. Preparation for transplantation included a target hemoglobin S level of ≤45%. Neutrophil engraftment (absolute neutrophil count >0.5 × 103/mL) was achieved at a median of 13 days (range, 10 to 34 days), and platelet engraftment (>50 × 103/mL) was achieved at a median of 19 days (range, 12 to 71 days). The median duration of inpatient hospitalization following stem cell infusion (day 0) was 21.5 days (range, 11 to 33 days). No patient developed SCD-related complications following G-CSF use. The most common organ toxicities encountered between G-CSF initiation (on day +7) and day +100 were anorexia (n = 14), hypertension (n = 11), and electrolyte imbalance requiring correction (n = 9). Central nervous system-related events were noted in 5 patients, all of whom had preexisting cerebral vasculopathy/moyamoya disease, attributed to reversible posterior leukoencephalopathy syndrome in the presence of calcineurin inhibitor therapy and hypertension. We conclude that G-CSF does not adversely impact SCD HSCT recipients and can be safely used post-transplantation to enhance neutrophil recovery.

Bone marrow transplant using fludarabine-based reduced intensity conditioning regimen with in vivo T cell depletion in patients with Fanconi anemia.

FA is the most common cause of inherited BMF syndromes. The only cure for BMF in FA remains HSCT. Due to DNA instability in FA, RIC has been used to decrease immediate and late complications of HSCT. Most FA conditioning regimens in mismatched and unrelated donor transplants rely on TBI, which increases the risk of secondary malignancies. Most of the non-TBI conditioning regimens use an ex vivo T-cell depletion approach, but this is not feasible at all pediatric stem cell transplant programs. To evaluate the success of HSCT in patients with FA using non-TBI conditioning regimens with in vivo T-cell depletion approach. HSCT using non-TBI based conditioning was performed on two siblings with FA. The first sibling underwent matched unrelated donor transplant with a BM graft using fludarabine, alemtuzumab, busulfan, and cyclophosphamide conditioning and cyclosporine and mycophenolate as GVHD prophylaxis. The second sibling underwent MSD transplant with UCB and BM grafts using similar approach, but without busulfan and mycophenolate. Both siblings had engraftment without signs of acute or chronic GVHD. Acute post-transplant complications included brief viral reactivations. At last follow-up, both siblings continued to have full immune reconstitution with stable chimerism. Conditioning regimens without radiation and inclusion of alemtuzumab can lead to successful engraftment without development of GVHD and reduce risk of developing secondary neoplasms, even with unrelated donor transplants.

Reduced-toxicity allogeneic hematopoietic stem cell transplantation in congenital sideroblastic anemia.

The case of an infant girl with severe congenital sideroblastic anemia associated with a novel molecular defect in mitochondrial transporter SLC25A38 is presented. Her transfusion dependence was fully reversed following allogeneic hematopoietic stem cell transplantation using a modified reduced-intensity conditioning regimen, and she remains healthy 5 years posttransplant.

Diffuse intrinsic brainstem tumors in neonates. Report of two cases.

The authors report on 2 newborn infants with the unusual presentation of intrinsic brainstem tumors. Both nondysmorphic, full-term neonates had cranial nerve palsies and hypotonia. Diagnoses of diffuse intrinsic brainstem gliomas were made on the basis of magnetic resonance imaging, which showed large expansive, nonenhancing intrinsic pontine masses. Intrinsic pontine tumors, characteristically seen in school-age children, are most often high-grade gliomas that are almost invariably fatal. However, the microanatomy and natural history of pontine tumors in neonates are unknown. With parental consent, both newborns were treated expectantly with supportive care but died of progressive disease by 2 weeks of age. In one child, postmortem examination revealed a primary brainstem primitive neuroectodermal tumor. The authors conclude that, as in older children, neonatal intrinsic brainstem tumors may be of a highly malignant nature. The rapid tumor progression in both cases indicates that where a diagnostic procedure may pose significant risks, supportive observation can aid in distinguishing malignant from benign tumor growth.

Use of sentinel lymph node biopsy and high-dose interferon in pediatric patients with high-risk melanoma: the Hospital for Sick Children experience.

BACKGROUND: Melanoma comprises less than 3% of all cancers seen in children. Sentinel lymph node biopsy (SLNBX) is an important predictor of outcome in adult melanoma and has not been widely used in pediatrics. Furthermore, adjuvant interferon has only been rarely used in childhood high-risk disease. OBJECTIVE: To review our experience with high-risk melanoma, the feasibility of SLNBX and the tolerance of high-dose interferon (HDI) therapy. METHODS: We retrospectively reviewed the medical records of patients with the diagnosis of cutaneous melanoma at our center over a 10-year period. RESULTS: Eleven patients were identified (median age of 12 y). Six of 10 patients who underwent SLNBX had disease in the lymph nodes and no complications from this procedure were observed. After complete lymph node dissection in these 6 patients, 1 developed wound infection and 2 had chronic lymph edema. Five patients were treated with adjuvant HDI of whom 2 patients required dose modification due to myelosuppression and liver toxicity. After a median follow-up of 26 months, 10 out of 11 patients are in remission. CONCLUSIONS: SLNBX is feasible and safe in pediatric melanoma and offers the potential to identify patients at high risk for disease progression who could benefit from HDI.