A multicenter report on the safety and efficacy of plerixafor based stem cell mobilization in children with malignant disorders.

BACKGROUND: Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent. STUDY DESIGN AND METHODS: In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34 + < 2 × 106 /kg) (Group B2) following failed SM and first apheresis attempts. RESULTS: The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted. CONCLUSION: Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.

Mycophenolate mofetil administered every 8 hours in combination with tacrolimus is efficacious in the prophylaxis of acute graft versus host disease in childhood, adolescent, and young adult allogeneic stem cell transplantation recipients.

BACKGROUND: The optimal dose and schedule of mycophenolate mofetil (MMF) in pediatric allogeneic stem cell transplant recipients remains to be determined. We previously reported safety and pharmacokinetics of MMF at 900 mg/m2 q6h dosing. This study was conducted to investigate the efficacy of tacrolimus plus q8h MMF dosing for acute graft versus host disease (GVHD) prophylaxis in a heterogeneous population of children, adolescent, young adult allogeneic stem cell transplant recipients, utilizing multiple allogeneic donor sources. PROCEDURE: GVHD prophylaxis consisted of tacrolimus 0.03-0.04 mg/kg/day intravenous continuous infusion or 0.12-0.16 mg/kg/day orally divided q8-12h and MMF 900 mg/m2 /dose (max. 1.5 g) or 15 mg/kg/dose intravenous/orally (age ≥18 years) q8h starting on Day +1. MMF was discontinued on Day +30 or Day +60 in the absence of acute GVHD. Thirty-five children, adolescents, and young adult allogeneic stem cell transplant recipients with malignant and nonmalignant disorders were enrolled. RESULTS: Kaplan-Meier probability of grade II-IV and grade III-IV acute GVHD was 22.8% (CI95 : 5.2-47.9 [where CI stands for confidence interval]) and 5.7% (CI95 : 0-48.9), respectively. Probability of extensive and limited chronic GVHD was 22.6% (CI95 : 3.4-52.2) and 12.2% (CI95 : 0.3-45.7), respectively. Probability of 1 year overall survival was 82% (CI95 : 64.1-99.8). Myeloablative conditioning was predictive of higher risk of acute GVHD in the univariate analysis (P = 0.01, hazard ratio = 6.6, CI95 : 0.91-48). CONCLUSION: This study demonstrated a low probability of acute and chronic GVHD in a diverse cohort of childhood, adolescent, and young adult allogeneic stem cell transplant recipients following MMF q8h plus tacrolimus prophylaxis.

Efficiently targeting neuroblastoma with the combination of anti-ROR1 CAR NK cells and N-803 in vitro and in vivo in NB xenografts.

The prognosis for children with recurrent and/or refractory neuroblastoma (NB) is dismal. The receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is highly expressed on the surface of NB cells, provides a potential target for novel immunotherapeutics. Anti-ROR1 chimeric antigen receptor engineered ex vivo expanded peripheral blood natural killer (anti-ROR1 CAR exPBNK) cells represent this approach. N-803 is an IL-15 superagonist with enhanced biological activity. In this study, we investigated the in vitro and in vivo anti-tumor effects of anti-ROR1 CAR exPBNK cells with or without N-803 against ROR1+ NB models. Compared to mock exPBNK cells, anti-ROR1 CAR exPBNK cells had significantly enhanced cytotoxicity against ROR1+ NB cells, and N-803 further increased cytotoxicity. High-dimensional analysis revealed that N-803 enhanced Stat5 phosphorylation and Ki67 levels in both exPBNK and anti-ROR1 CAR exPBNK cells with or without NB cells. In vivo, anti-ROR1 CAR exPBNK plus N-803 significantly (p < 0.05) enhanced survival in human ROR1+ NB xenografted NSG mice compared to anti-ROR1 CAR exPBNK alone. Our results provide the rationale for further development of anti-ROR1 CAR exPBNK cells plus N-803 as a novel combination immunotherapeutic for patients with recurrent and/or refractory ROR1+ NB.

Recurrent immune thrombocytopenic purpura in children.

Recurrent immune thrombocytopenic purpura (ITP) is defined as the recurrence of ITP after at least 3 months of remission sustained without treatment. Among 340 children with ITP, 14 had recurrent ITP (4.1%). Ten were females. The initial course was acute in 8 patients and chronic in 6. The median time to recurrence was 33 months (range 4-120). Only 1 patient had a second recurrence. Twelve (86%) achieved complete (n = 10) or partial (n = 2) remission, two of them after splenectomy. One patient continued to require treatment at 10 months from recurrence. One child died of intracranial hemorrhage despite aggressive treatment including splenectomy and craniotomy.

Acquired thrombotic thrombocytopenic purpura in children: a single institution experience.

OBJECTIVE: To describe the clinical features, treatment and prognosis of acquired thrombotic thrombocytopenic purpura (TTP) in children based on a single institution experience. METHODS: This study is a retrospective review of all 12 children with TTP seen at New York Medical College- Westchester Medical Center during a period of 15 y from 1993 to 2008. RESULTS: There were 7 females and 5 males with acquired TTP, with a median age of 13 (range, 6-17); and no cases of congenital TTP. The classic pentad of TTP (microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, renal dysfunction and fever) was seen in only three patients. Nine had renal involvement; eight had neurologic symptoms; and four had fever. All 12 patients had thrombocytopenia, anemia, and elevated LDH. Nine had idiopathic TTP. Three patients had one of the following underlying disorders: systemic lupus erythematosus, mixed connective tissue disorder, and aplastic anemia (post-bone marrow transplant on cyclosporine). ADAMTS13 level was decreased in 7 of 8 patients studied. Eight of 10 patients achieved remission with plasmapheresis alone. Two needed additional treatment before achieving remission. Two had one or more relapses, requiring immunosupressive treatment with vincrisine, prednisone, or rituximab. The patient with aplastic anemia died of pulmonary hypertension 5 y after bone marrow transplantation. All other 11 patients are alive and free of TTP for a median follow-up of 12 mo (range, 3-72 mo). CONCLUSIONS: Acquired pediatric TTP responds well to plasmapheresis. However, many patients do require additional treatment because of refractoriness to plasmapheresis or relapse. The clinical features, response to treatment, and relapse rate of pediatric TTP appear similar to those of adult TTP.

Neuroblastoma masquerading as cervical lymphadenitis.

Cervical lymphadenitis is a common pediatric finding prompting medical evaluation. The most common etiologies are infectious and reactive. The location of the involved lymph node group may provide clues to the origin of the underlying pathologic process. We describe a 21-month-old boy with metastatic neuroblastoma who presented with classic findings of infectious lymphadenitis. Surgical intervention and careful examination of histopathology led to this unexpected diagnosis.

Real-time quantitative PCR: standardized detection of minimal residual disease in pediatric acute lymphoblastic leukemia. Polymerase chain reaction.

PURPOSE: To develop a standardized real-time polymerase chain reaction (PCR) method of quantifying minimal residual disease (MRD) in patients with pre-B acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: In a series of 24 follow-up bone marrow (BM) samples in 11 patients (14 clonal markers), we performed real-time PCR assays using one consensus and one clone-specific primer for each marker. The markers analyzed included immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and TEL-AML1 rearrangements. RESULTS: We achieved a detection limit of 3.3 x 10(-5) +/- 1.2 x 10(-5) and an accurate quantitation (r = -0.99) limit of 2.0 x 10(-4) +/- 8.8 x 10(-5) blasts. Both inter- and intra-assay reproducibility were exceptional. Additionally, we found comparable results to those of a "gold standard" limiting-dilution PCR assay (r = 0.62). CONCLUSIONS: The IgH, TCR and TEL-AML1 markers can be used as targets by real-time PCR under the same cycling profile, allowing quantitation of MRD in more 95% of patients with pre-B ALL. This standardized, real-time PCR technique should simplify monitoring MRD in clinical trials.