FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia.

Tisagenlecleucel (Kymriah; Novartis Pharmaceuticals) is a CD19-directed genetically modified autologous T-cell immunotherapy. On August 30, 2017, the FDA approved tisagenlecleucel for treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory in second or later relapse. Approval was based on the complete remission (CR) rate, durability of CR, and minimal residual disease (MRD) <0.01% in a cohort of 63 children and young adults with relapsed or refractory ALL treated on a single-arm trial (CCTL019B2202). Treatment consisted of fludarabine and cyclophosphamide followed 2 to 14 days later by a single dose of tisagenlecleucel. The CR rate was 63% (95% confidence interval, 50%-75%), and all CRs had MRD <0.01%. With a median follow-up of 4.8 months, the median duration of response was not reached. Cytokine release syndrome (79%) and neurologic events (65%) were serious toxicities reported in the trial. With implementation of a Risk Evaluation and Mitigation Strategy, the benefit-risk profile was considered acceptable for this patient population with such resistant ALL. A study of safety with 15 years of follow-up is required as a condition of the approval.See related commentary by Geyer, p. 1133.

Recommendations for the return of research results to study participants and guardians: a report from the Children's Oncology Group.

PURPOSE: The Children's Oncology Group (COG) strongly supports the widely recognized principle that research participants should be offered a summary of study results. The mechanism by which to do so in a cooperative research group setting has not been previously described. METHODS: On the basis of a review of the available empirical and theoretic literature and on iterative, multidisciplinary discussion, a COG Return of Results Task Force (RRTF) offered detailed recommendations for the return of results to research study participants. RESULTS: The RRTF established guidelines for the notification of research participants and/or their parents/guardians about the availability of research results, a mechanism for and timing of sharing results via registration on the COG public Web site, the scope of the research to be shared, the target audience, and a process for creating and vetting lay summaries of study results. The RRTF recognized the challenges in adequately conveying complex scientific results to audiences with varying levels of health literacy and recommended that particularly sensitive or complex results be returned using direct personal contact. The RRTF also recommended evaluation of the cost, effectiveness, and impact of sharing results. CONCLUSION: These recommendations provide a framework for the offering and returning of results to participants. They can be used by individual investigators, multi-investigator research collaboratives, and large cooperative groups.

Outcomes for children and adolescents with cancer: challenges for the twenty-first century.

PURPOSE: This report provides an overview of current childhood cancer statistics to facilitate analysis of the impact of past research discoveries on outcome and provide essential information for prioritizing future research directions. METHODS: Incidence and survival data for childhood cancers came from the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries, and mortality data were based on deaths in the United States that were reported by states to the Centers for Disease Control and Prevention by underlying cause. RESULTS: Childhood cancer incidence rates increased significantly from 1975 through 2006, with increasing rates for acute lymphoblastic leukemia being most notable. Childhood cancer mortality rates declined by more than 50% between 1975 and 2006. For leukemias and lymphomas, significantly decreasing mortality rates were observed throughout the 32-year period, though the rate of decline slowed somewhat after 1998. For remaining childhood cancers, significantly decreasing mortality rates were observed from 1975 to 1996, with stable rates from 1996 through 2006. Increased survival rates were observed for all categories of childhood cancers studied, with the extent and temporal pace of the increases varying by diagnosis. CONCLUSION: When 1975 age-specific death rates for children are used as a baseline, approximately 38,000 childhood malignant cancer deaths were averted in the United States from 1975 through 2006 as a result of more effective treatments identified and applied during this period. Continued success in reducing childhood cancer mortality will require new treatment paradigms building on an increased understanding of the molecular processes that promote growth and survival of specific childhood cancers.

Progress in childhood cancer: 50 years of research collaboration, a report from the Children's Oncology Group.

The Children's Oncology Group (COG) recently celebrated the milestone of 50 years of pediatric clinical trials and collaborative research in oncology. Our group had its origins in the four legacy pediatric clinical trials groups: the Children's Cancer Group (CCG), the Pediatric Oncology Group (POG), the National Wilms' Tumor Study Group (NWTS), and the Intergroup Rhabdomyosarcoma Study Group (IRSG), which merged in 2000 to form the COG. Over the last 50 years, the survival rates for childhood cancer have risen from 10% to almost 80%. Outcome in acute lymphoblastic leukemia (ALL) has gone from a 6-month median survival to an 80% overall cure rate. We have modified therapies in most major diseases to induce remission with the fewest long-term sequelae. Here we look back on our advances but also look forward to the next 50 years, which will produce even more successful treatments that will be tailored to the specific patient, translating the tools of molecular genetics. Experience has clearly proven that everything we know about the diagnosis and management of childhood cancer is a result of research and the dramatic historical decrease in mortality from childhood cancer is directly related to cooperative group clinical research.

Health knowledge about symptoms of heart attack and stroke in adult survivors of childhood acute lymphoblastic leukemia.

PURPOSE: Children with acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, have a 5-year survival rate of better than 80%. Long-term survivors of childhood ALL, however, carry an elevated risk of early mortality from cardiac events and stroke and a disproportionately high prevalence of dyslipidemia and obesity, presumably as an adverse effect of treatment. METHODS: As part of a clinical follow-up study of 70 young adult survivors of childhood ALL, we evaluated the degree to which this high-risk group differed in knowledge about symptoms of heart attack and stroke from that of a population-based comparison group frequency-matched by age, sex, and body mass index. Questions from the Behavioral Risk Factor Surveillance System were used to assess health knowledge. RESULTS: Survivors of ALL scored considerably worse on symptom knowledge than did their population counterparts. The strongest association was observed for chest pain as a symptom of heart attack: ALL survivors were 14-fold more likely than the comparison group to answer the question incorrectly. Seventy-seven percent of survivors failed to identify pain in the jaw, neck, or back as a heart attack symptom. CONCLUSIONS: These results indicate an important gap in knowledge and underscore the need for health education among survivors of childhood leukemia that includes information about symptoms of myocardial infarction and stroke.

Metabolic syndrome and growth hormone deficiency in adult survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: The purpose of the study was to determine the prevalence of metabolic syndrome, growth hormone deficiency, and cardiovascular risk factors among adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with or without cranial irradiation. METHODS: Follow-up was undertaken of 75 randomly selected long-term childhood ALL survivors. Testing included fasting insulin, glucose, lipids, and growth hormone (GH) releasing hormone plus arginine stimulation test. The prevalence of metabolic syndrome was compared with population norms from 1999-2002 National Health and Nutrition Examination Study (NHANES) data, and internally between those with and without past cranial irradiation and those with normal (>16.5 microg/L) versus insufficient (9-16.5 microg/L) versus deficient (<9 microg/L) peak GH secretion. RESULTS: The mean subject age was 30 years and the mean time since ALL diagnosis was 25 years. The prevalence of metabolic syndrome did not differ statistically (P = .87) between study subjects (16.6%) and same-age, same-sex population norms (17.5%). However, 60% of subjects treated with cranial irradiation, compared with 20% of those who were not, had 2 or more of the 5 components of metabolic syndrome. Untreated abnormally low GH was present in 64% of subjects overall and 85% of those who received past cranial irradiation. Cranial irradiation was strongly related to GH deficiency, and in turn lower insulin-like growth factor 1 (IGF-1), higher fasting insulin, abdominal obesity, and dyslipidemia, particularly in women. CONCLUSIONS: Hematologists who treat childhood ALL patients, and particularly those who provide primary care to adult survivors, should be aware of the potential for long-term GH deficiency and adverse cardiovascular and diabetes risk profiles as a consequence of leukemia treatment.

Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study.

PURPOSE: The long-term survival of children between age 12 and 24 months with stage 4 neuroblastoma and nonamplified MYCN (MYCN-NA) has not been defined previously. PATIENTS AND METHODS: Survival for stage 4 MYCN-NA neuroblastoma patients enrolled onto Children's Cancer Group (CCG) protocols 321P2 (1986 to 1991) and 3891 (1991 to 1996) was analyzed. Treatment consisted of intensive alkylator-based induction chemotherapy with or without autologous bone marrow transplantation (ABMT) with or without 13 cis-retinoic acid. Survival was analyzed by age strata less than 12, 12 to 18, 18 to 24, and more than 24 months at diagnosis. Patients younger than 12 months were treated on the moderate-intensity CCG protocol 3881. RESULTS: Forty-three patients with stage 4 MYCN-NA disease enrolled onto CCG-321P2 (n = 17) or CCG-3891 (n = 26) were between 12 and 24 months of age at diagnosis. After a median follow-up of 94 months (range, 4 to 140 months), the 6-year event-free survival (EFS) for the 12- to 18-month age group was superior to that of the 18- to 24-month age group (74% +/- 8% v 31% +/- 12%; P = .008). The EFS for children older than 24 months with stage 4 MYCN-NA neuroblastoma was 23% +/- 3%, and for children younger than 12 months was 92% +/- 3%. CONCLUSION: Children diagnosed with stage 4 MYCN-NA neuroblastoma in the second year of life form a transitional group between infants and older children in terms of prognosis. Patients between 12 and 18 months of age have significantly better long-term survival than that of older children treated with intensive chemotherapy with or without ABMT. These patients may not benefit from additional intensification of therapy beyond that provided in earlier clinical trials and may even maintain this high survival rate with less intensive therapy.