FDA approval summary: Crizotinib for pediatric and young adult patients with relapsed or refractory systemic anaplastic large cell lymphoma.

In January 2021, the U.S. Food and Drug Administration (FDA) approved crizotinib for pediatric patients 1 year and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). This is the first approval for pediatric sALCL. Approval was based on a single-arm trial of crizotinib monotherapy that included 26 patients, aged 1-20 years, with previously treated sALCL. Efficacy was based on centrally assessed objective response rate (88%) and duration of response. Herein, we highlight unique aspects of the regulatory review, including extension of the indication to young adults, postmarketing safety, and dose optimization strategies.

FDA approval summary: Dalteparin for the treatment of symptomatic venous thromboembolism in pediatric patients.

On May 16, 2019, the U.S. Food and Drug Administration (FDA) approved dalteparin sodium for the treatment of symptomatic venous thromboembolism (VTE) to reduce the risk of recurrence in pediatric patients 1 month of age and older. Approval was primarily based on FDA review of a single-arm trial evaluating dalteparin administered subcutaneous twice daily in 38 pediatric patients with symptomatic VTE. Efficacy was based on the achievement of therapeutic plasma anti-Xa levels. The FDA concluded that dalteparin has efficacy and acceptable safety for pediatric patients.

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.

Dissociation of Pubertal Development Abnormality and Gonadal Dysfunction in Childhood Cancer Survivors.

Purpose: To determine the relationship between pubertal development and postpubertal gonadal function in childhood cancer survivors. Methods: Childhood cancer survivors (≥10 years of age) who received follow-up care in a pediatric oncology group in an academic medical center during the period from January 1, 1985, to July 1, 2010 were included in this case series. Their pubertal development and gonadal function were evaluated. Results: The cohort consists of 39 males (age 10-21 years) and 35 females (age 10-29 years) with a variety of cancer diagnosis and treatments. The average age at diagnosis was ∼7.5 years. The average age at the time of the study was 16 and 16.7 years in males and females, respectively, representing a mean follow-up interval of ∼9 years. Despite the fact that 60% of survivors received cyclophosphamide equivalents and 16.2% received cranial radiation or brain tumor resection, the majority of survivors (68%) presented with both normal puberty and normal gonadal functions at the time of follow-up. In 27% of survivors, puberty development did not predict gonadal function in early adulthood: 20% of survivors had normal puberty, but abnormal gonadal function; 7% of survivors had abnormal puberty, but gonadal function remained normal as young adults. Conclusions: Most childhood cancer survivors had normal puberty and gonadal function despite a variety of cancer treatment modalities. However, normal puberty did not predict normal gonadal function later in life in many survivors. Therefore, close follow-up with gonadal function in adolescent and early adulthood years is essential.

A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas.

PURPOSE: Patients with metastatic or recurrent Ewing's sarcoma family of tumors and alveolar rhabdomyosarcoma have <25% 5-year survival in most studies. This study administered a novel immunotherapy regimen aimed at consolidating remission in these patients. EXPERIMENTAL DESIGN: Fifty-two patients with translocation positive, recurrent, or metastatic Ewing's sarcoma family of tumors or alveolar rhabdomyosarcoma underwent prechemotherapy cell harvest via apheresis for potential receipt of immunotherapy. Following completion of standard multimodal therapy, 30 patients ultimately initiated immunotherapy and were sequentially assigned to three cohorts. All cohorts received autologous T cells, influenza vaccinations, and dendritic cells pulsed with peptides derived from tumor-specific translocation breakpoints and E7, a peptide known to bind HLA-A2. Cohort 1 received moderate-dose recombinant human interleukin-2 (rhIL-2), cohort 2 received low-dose rhIL-2, and cohort 3 did not receive rhIL-2. RESULTS: All immunotherapy recipients generated influenza-specific immune responses, whereas immune responses to the translocation breakpoint peptides occurred in 39%, and only 25% of HLA-A2(+) patients developed E7-specific responses. Toxicity was minimal. Intention-to-treat analysis revealed a 31% 5-year overall survival for all patients apheresed (median potential follow-up 7.3 years) with a 43% 5-year overall survival for patients initiating immunotherapy. CONCLUSIONS: Consolidative immunotherapy is a scientifically based and clinically practical approach for integrating immunotherapy into a multimodal regimen for chemoresponsive cancer. Patients receiving immunotherapy experienced minimal toxicity and favorable survival. The robust influenza immune responses observed suggest that postchemotherapy immune incompetence will not fundamentally limit this approach. Future studies will seek to increase efficacy by using more immunogenic antigens and more potent dendritic cells.