Access to innovative therapies in pediatric oncology: Report of the nationwide experience in Canada.

BACKGROUND: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. METHODS: Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. RESULTS: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi-targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA-mTOR-AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. CONCLUSION: This real-world data collection illustrates an increasing use of "out-of-trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.

Rhabdomyosarcoma as the first presentation in Neurofibromatosis Type 1: case series and review of the literature.

Neurofibromatosis Type 1 (NF1) is a neurocutaneous syndrome characterized by multiple café-au-lait macules, neurofibromas, and predisposition to malignancies, including rhabdomyosarcomas (RMS). Somatic NF1 mutations occur in RMS and other cancers, and ∼1% of patients with RMS have NF1. We describe three patients who presented prior to one year of age with RMS and were subsequently diagnosed with NF1. Compared to sporadic RMS, patients with this cancer predisposition syndrome are diagnosed younger, genitourinary sites are more common, and tumors are almost exclusively the embryonal subtype. Genomic sequencing of the tumor was initiated in one patient, and we identified a second sequence variant in NF1. The identification of molecular drivers in tumors is changing the nature of pediatric oncology by informing therapeutics targeted to specific molecular pathways and selecting patients who are likely to harbor germline variants in cancer predisposition genes who would benefit from a Medical Genetics assessment.

Does age play a role in fever and neutropenia events and complications: A comparison of adolescents versus younger children with cancer at a tertiary care pediatric hospital, a pilot project.

BACKGROUND: Adolescents and young adults with cancer (AYA) are a complex group of patients. The development of fever and neutropenia (FN) is a potentially lethal complication of chemotherapy. Risk stratification of patients with FN has become increasingly valuable allowing for early intervention and to guide treatment type and duration appropriately. There are risk stratification guidelines that exist, but most are validated in young children with cancer (YCWC). AYA are frequently shown to have more numerous and severe side effects from chemotherapy. AIMS: This study aimed to identify whether age contributes to the incidence and severity of FN. METHODS AND RESULTS: Patients diagnosed with a malignancy in a 5-year period at our institution were included from ages 0-18 years. We reviewed details of their FN events, including duration of hospital admission, source (bacterial/fungal), PICU admission and duration, positive blood cultures and mortality. Adolescents with cancer (AWC) had a trend of being 1.56 times more likely to have FN events (CI 95% 0.936-2.622, p = 0.087). Assessment of the duration of PICU stay showed that AWC were 4.9 times more likely to have longer admissions (CI 95% 0.998-24.067, p = 0.050). There was no significant difference between the two groups in the rate of PICU admission, positive cultures, identification of a bacterial or fungal source, hospital admission duration or mortality from FN. CONCLUSION: This study demonstrated a trend towards AWC being more likely to develop FN events. When such events occur in this group, the severity of them may be heightened as evidenced by longer duration of PICU admission.

Reduction of Extramedullary Complications in Patients With Acute Myeloid Leukemia/Myelodysplastic Syndrome Treated With Azacitidine.

The distinction between myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) often relies on an arbitrary marrow blast cutoff of 30% in pediatrics and 20% in adults. There is little data about the treatment of children with extramedullary myeloid malignancy that has features of both, MDS and AML. Herein, we report for the first time 2 patients MDS/AML (1 with Shwachman-Diamond syndrome and 1 with idiopathic MDS and monosomy 7) who presented with extramedullary complications, received treatment with azacitidine, achieved complete remission and subsequently underwent hematopoietic stem cell transplantation.

Allergic Reactions Associated with Intravenous Versus Intramuscular Pegaspargase: A Retrospective Chart Review.

BACKGROUND: Pegaspargase (PEG-ASP) is essential chemotherapy for acute lymphoblastic leukemia (ALL). Since changing to intravenous (IV) administration from intramuscular (IM), an increased number of allergic reactions have been anecdotally noted at our institution. This study compares the rate and severity of allergic reactions in children receiving IM or IV PEG-ASP. METHODS: We performed a retrospective chart review of patients treated with IV or IM PEG-ASP at The Hospital for Sick Children, Toronto, Canada, from March 1, 2010 to January 1, 2012. The incidence and severity of allergic reactions attributed to PEG-ASP were documented. Patient age, sex, route of PEG-ASP administration, disease (risk group and lineage) and mean time interval between PEG-ASP doses were evaluated as possible risk factors for allergic reaction. RESULTS: A total of 109 patients were included. There were 14 (35 %) allergic reactions among 40 patients who received IV, compared with eight (12 %) of the 69 who received IM [odds ratio (OR) 4.11, 95 % confidence interval (CI) 1.54-10.97, p = 0.005]. In multivariable logistic regression adjusting for disease risk group, route (IV vs. IM) remained independently significant (p = 0.011). Patients with standard-risk ALL had a lower risk of experiencing an allergic reaction associated with PEG-ASP compared with patients in high-risk disease risk groups (collectively referred to as "other"; 11 vs. 31 %, OR 3.36, 95 % CI 1.16-9.72, p = 0.025). CONCLUSIONS: IV PEG-ASP is associated with a significantly higher rate of allergic reactions than IM. The clinical preference for IV PEG-ASP may warrant re-evaluation.

Optimal management of Ewing sarcoma family of tumors: recent developments in systemic therapy.

The Ewing sarcoma family of tumors (ESFT) is defined by cell surface expression of CD99 and a translocation involving EWS and an ETS partner. Cytotoxic chemotherapy remains the benchmark of first- and second-line therapy, and although the majority of patients with localized disease are cured, almost one third of patients relapse or progress from their disease. Moreover, cure remains elusive in most patients who present with distant metastases. In recent years, the ESFT literature has been dominated by reports of attempts at modulating the insulin-like growth factor (IGF) receptor (IGFR). Unfortunately, three phase II studies examining inhibiting antibodies to IGFR-1 published disappointing results. Whether these results were due to failure to modulate the pathway or other limitations in study design and/or patient selection remain unclear. Other novel strategies currently being investigated in ESFT include tyrosine kinase, mammalian target of rapamycin (mTOR), and poly(ADP-ribose) polymerase (PARP) inhibitors.

The impact of prophylactic fresh-frozen plasma and cryoprecipitate on the incidence of central nervous system thrombosis and hemorrhage in children with acute lymphoblastic leukemia receiving asparaginase.

Asparaginase (ASP) therapy is associated with depletion of antithrombin (AT) and fibrinogen (FG). Potential toxicities include central nervous system thrombosis (CNST) and hemorrhage. Historical practice at the Izaak Walton Killam Health Centre (IWK) involves measuring AT and FG levels after ASP administration and transfusing fresh-frozen plasma (FFP) or cryoprecipitate (CRY) to prevent thrombotic and hemorrhagic complications. To determine whether this reduced these complications in children with acute lymphoblastic leukemia (ALL), incidence, outcome, and clinical characteristics of ASP-related CNST in ALL patients at IWK were compared with a similar cohort from BC Children's Hospital (BCCH), where prophylaxis was not performed. Costs associated with preventative versus expectant management were estimated. From 1990 to 2005, 240 patients were treated at IWK and 479 at BCCH. Seven BCCH patients developed venous CNST (1.5%), compared with none at IWK. CNST occurred exclusively during induction. Six patients received anticoagulation and continued ASP. All 7 patients remain in remission. National Cancer Institute high-risk ALL predicted CNST risk (P = .02), whereas sex, age, race, and body mass index did not. Neither FFP nor CRY protected against CNST, suggesting prophylaxis is unwarranted for unselected ALL patients. However, prophylactic replacement for HR patients in induction may be cost-effective.