Risk Factors for Transplant-Associated Thrombotic Microangiopathy after Autologous Hematopoietic Cell Transplant in High-Risk Neuroblastoma.

High-risk neuroblastoma has a poor prognosis, and research studies have shown that increasing the intensity of therapy improves outcomes. Autologous hematopoietic cell transplant (aHCT) as consolidation therapy confers a significant survival advantage but is accompanied by significant morbidity. Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication caused by endothelial injury that often leads to hemolytic anemia, microthrombotic platelet consumption, and renal injury. Here we investigated the incidence, potential risk factors, and sequelae of TA-TMA in patients with high-risk neuroblastoma. We conducted a retrospective chart review of all patients (n = 141) with neuroblastoma in our institutions who underwent aHCT from 2000 to 2017. Ten patients (7%) developed TA-TMA. The patients in the TA-TMA group were similar to the rest of the subjects in demographics, disease burden, prior therapies, renal function, and timing of transplant. The type of conditioning regimen was the only statistically significant pretransplant variable (P < .001). Six of 15 patients (40%) intended to receive tandem transplants (cyclophosphamide/thiotepa and then carboplatin/etoposide/melphalan (CEM)), 4 of 68 patients (6%) who received conditioning with single CEM, and none of the 56 patients who received busulfan/melphalan were diagnosed with TA-TMA. Patients with TA-TMA were more likely to require intensive care unit transfer, have a longer length of stay in the hospital, and experience a delay or change in their subsequent therapy. In our cohort overall, patients with a delay in therapy after transplant appeared to have a worse overall survival, although the difference was not statistically significant. Because of this high incidence and significant morbidity, we have implemented standardized screening for TA-TMA during and after transplant. We anticipate that screening will lead to earlier intervention and decreased severity of disease.

Neuroblastoma: clinical and biological approach to risk stratification and treatment.

Neuroblastoma is the most common extra-cranial solid tumor of childhood and the most common in the first year of life. It is a unique malignancy in that infants often present with either localized or metastatic disease that can spontaneously regress without intervention while older children can succumb to the disease after months to years of arduous therapy. Given this wide range of outcomes, the International Neuroblastoma Risk Group was created to stratify patients based on presenting characteristics and tumor biology in order to guide intensity of treatment strategies. The goal has been to decrease therapy for low-risk patients to avoid long-term complications while augmenting and targeting therapies for high-risk patients to improve overall survival. The international risk stratification depends on age, stage, histology, MYCN gene amplification status, tumor cell ploidy and segmental chromosomal abnormalities. Treatment for asymptomatic low-risk patients with an estimated survival of > 98% is often observation or surgical resection alone, whereas intermediate-risk patients with an estimated survival of > 90% require moderate doses of response-adjusted chemotherapy along with resection. High-risk patients undergo multiple cycles of combination chemotherapy before surgery, followed by consolidation with myeloablative autologous hematopoietic stem cell transplantation and local radiation and finally immunotherapy with differentiation therapy as maintenance phase. With this approach, outcome for patients with neuroblastoma has improved, as the field continues to expand efforts in more targeted therapies for high-risk patients.

Genetic susceptibility to neuroblastoma.

Until recently, the genetic basis of neuroblastoma, a heterogeneous neoplasm arising from the developing sympathetic nervous system, remained undefined. The discovery of gain-of-function mutations in the ALK receptor tyrosine kinase gene as the major cause of familial neuroblastoma led to the discovery of identical somatic mutations and rapid advancement of ALK as a tractable therapeutic target. Inactivating mutations in a master regulator of neural crest development, PHOX2B, have also been identified in a subset of familial neuroblastomas. Other high penetrance susceptibility alleles likely exist, but together these heritable mutations account for less than 10% of neuroblastoma cases. A genome-wide association study of a large neuroblastoma cohort identified common and rare polymorphisms highly associated with the disease. Ongoing resequencing efforts aim to further define the genetic landscape of neuroblastoma.

Treatment-related adverse events associated with a modified UK ALLR3 induction chemotherapy backbone for childhood relapsed/refractory acute lymphoblastic leukemia.

BACKGROUND: The UK ALLR3 (R3) regimen has been adopted to treat pediatric relapsed acute lymphoblastic leukemia (ALL) by many centers in the United States and has become a preferred therapeutic backbone for testing novel agents in clinical trials. A detailed toxicity profile of this platform has not previously been reported. The toxicity and response rates for its use beyond first relapse are unknown. PROCEDURES: We performed a multi-institutional, retrospective study including children with relapsed ALL treated with the R3 reinduction chemotherapy backbone block 1 across five pediatric centers. Data were extracted from medical records and analyzed. RESULTS: Fifty-nine patients were included in the study, including 16 patients with ≥2nd relapse. Ninety-seven percent of patients experienced at least one Grade ≥3 nonhematologic adverse event (AE). Grade 3 or higher infection was reported in 90% of patients. Other nonhematologic Grade ≥3 AEs included electrolyte abnormalities, elevation in hepatic enzymes, and pain. Eighty-five percent of patients achieved a complete remission (CR). There were no significant differences in the incidence of AEs, CR rate, and rate of minimal residual disease negativity between patients with 1st or ≥2nd relapse. CONCLUSION: Our study confirmed that R3 block 1 is a highly active reinduction regimen in childhood relapsed ALL. However, it was associated with a high incidence of severe toxicities, particularly infection. The toxicity profiled in our report should be used to inform optimal supportive care and future clinical trial design with the R3 backbone, particularly when new agents are combined with this regimen.