Introduction
In several studies, the chimeric antigen receptor T‐cell therapy tisagenlecleucel demonstrated encouraging rates of remission and lasting survival benefits in pediatric patients with ...relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). We assessed the cost‐effectiveness of tisagenlecleucel (list price: 320 000 EUR) among these patients when compared to clofarabine monotherapy (Clo‐M), clofarabine combination therapy (Clo‐C), and blinatumomab (Blina) from both a healthcare and a societal perspective. We also assessed future medical and future non‐medical consumption costs.
Methods
A three‐state partitioned survival model was used to simulate a cohort of pediatric patients (12 years of age) through different disease states until the end of life (lifetime horizon). Relevant outcomes were life years, quality‐adjusted life years (QALYs), healthcare costs, societal costs, and the incremental cost‐effectiveness ratio (ICER). Uncertainty was explored through deterministic and probabilistic sensitivity analyses as well as through several scenario analyzes.
Results
Total discounted costs for tisagenlecleucel were 552 679 EUR from a societal perspective, which was much higher than the total discounted costs from a healthcare perspective (ie, 409 563 EUR). Total discounted societal costs for the comparator regimens ranged between 160 803 EUR for Clo‐M and 267 259 EUR for Blina. Highest QALYs were estimated for tisagenlecleucel (11.26), followed by Blina (2.25), Clo‐C (1.70) and Clo‐M (0.74). Discounted societal ICERs of tisagenlecleucel ranged between 31 682 EUR/QALY for Blina and 37 531 EUR/QALY for Clo‐C and were considered cost‐effective with a willingness‐to‐pay (WTP) threshold of 80 000 EUR/QALY. None of the scenarios exceeded this threshold, and more than 98% of the iterations in the probabilistic sensitivity analysis were cost‐effective.
Discussion
At the current price and WTP threshold, tisagenlecleucel is cost‐effective from both a healthcare and a societal perspective. Nevertheless, long‐term effectiveness data are needed to validate the several assumptions that were necessary for this model.
Guidelines in paediatric oncology encourage health care providers to share relevant information with young patients and parents to enable their active participation in decision making. It is not ...clear to what extent this mirrors patients' and parents' preferences. This study investigated communication preferences of childhood cancer patients, parents, and survivors of childhood cancer.
Communication preferences were examined by means of online focus groups. Seven patients (aged 8-17), 11 parents, and 18 survivors (aged 8-17 at diagnosis) participated. Recruitment took place by consecutive inclusion in two Dutch university oncological wards. Questions concerned preferences regarding interpersonal relationships, information exchange and participation in decision making.
Participants expressed detailed and multi-faceted views regarding their needs and preferences in communication in paediatric oncology. They agreed on the importance of several interpersonal and informational aspects of communication, such as honesty, support, and the need to be fully informed. Participants generally preferred a collaborative role in medical decision making. Differences in views were found regarding the desirability of the patient's presence during consultations. Patients differed in their satisfaction with their parents' role as managers of the communication.
Young patients' preferences mainly concur with current guidelines of providing them with medical information and enabling their participation in medical decision making. Still, some variation in preferences was found, which faces health care providers with the task of balancing between the sometimes conflicting preferences of young cancer patients and their parents.
Objective
The KLIK method is an online tool that monitors and discusses electronic patient‐reported outcomes (ePROs), which has been shown to enhance outcomes. This study aimed (1) to determine the ...fidelity (ie, extent to which used as intended) of the KLIK method as implemented in outpatient pediatric cancer care and (2) to study health care professional (HCP)‐reported barriers and facilitators for implementation.
Methods
Two hundred five children with newly diagnosed cancer (enrollment rate 85%) participated. At 1 (T1), 3 (T2), and 6 (T3) months after diagnosis, patients (8‐18 years) or parents (of patients 0‐7 years) completed health‐related quality of life (HRQoL) questionnaires, which were transformed into an ePROfile and discussed by their HCP during consultations. Fidelity was determined by the following: percentage of website registrations, HRQoL questionnaires completed, and ePROfiles discussed. Implementation determinants were assessed with HCPs after the final T3 with the Measurement Instrument for Determinants of Innovations.
Results
Depending on the time point (T1‐T3), fidelity was 86% to 89% for website registration, 66‐85% for completed HRQoL questionnaires, and 56% to 62% for ePROfile discussion. Barriers were mainly related to organizational issues (eg, organizational change) and less frequently to users (eg, motivation to comply) or the intervention (compatibility). Facilitators were related to the user (eg, positive outcome expectations) and intervention (simplicity) but not to the organization.
Conclusions
When implementing ePROs in outpatient pediatric oncology practice, HCPs report determinants that influence ePRO integration. To improve implementation and outcomes, tailored organizational (eg, formal ratification by management and time) and specific local (eg, individualized assessments) strategies should be developed to achieve optimal ePRO discussion.
Neuroblastoma is a childhood malignancy and in the majority of patients, the primary tumor arises in one of the adrenal glands. Neuroblastoma cells highly express the disialoganglioside GD2, which is ...the primary target for the development of neuroblastoma immunotherapy. Anti-GD2 mAbs have shown clinical efficacy and are integrated into standard treatment for high-risk neuroblastoma patients. We previously reported synergy between the HDAC inhibitor Vorinostat and anti-GD2 mAbs in a heterotopic, subcutaneous growing neuroblastoma model. Additionally, we have previously developed an orthotopic intra-adrenal neuroblastoma model showing more aggressive tumor growth. Here, we report that anti-GD2 mAb and Vorinostat immunocombination therapy is even more effective in suppressing neuroblastoma growth in the aggressive orthotopic model, resulting in increased animal survival. Intra-adrenal tumors from mice treated with Vorinostat were highly infiltrated with myeloid cells, including macrophages, displaying increased MHCII and Fc-receptor expression. Collectively, these data provide a strong rationale for clinical testing of anti-GD2 mAbs with concomitant Vorinostat in neuroblastoma patients.
COVID-19 vaccinations are recommended for children with cancer but data on their vaccination response is scarce. This study assesses the antibody and T-cell response following a 2- or 3-dose ...vaccination with BNT162b2 mRNA COVID-19 vaccine in children (5-17 years) with cancer. For the antibody response, participants with a serum concentration of anti-SARS-CoV-2 spike 1 antibodies of >300 binding antibody units per milliliter were classified as good responders. For the T-cell response, categorization was based on spike S1 specific interferon-gamma release with good responders having >200 milli-international units per milliliter. The patients were categorized as being treated with chemo/immunotherapy for less than 6 weeks (Tx < 6 weeks) or more than 6 weeks (Tx > 6 weeks) before the first immunization event. In 46 patients given a 2-dose vaccination series, the percentage of good antibody and good T-cell responders was 39.3% and 73.7% in patients with Tx < 6 weeks and 94.4% and 100% in patients with Tx > 6 weeks, respectively. An additional 3rd vaccination in 16 patients with Tx < 6 weeks, increased the percentage of good antibody responders to 70% with no change in T-cell response. A 3-dose vaccination series effectively boosted antibody levels and is of value for patients undergoing active cancer treatment.
The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assessment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during ...and shortly after treatment with anthracyclines.
Cardiac function of 60 children with ALL was prospectively studied with measurements of cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and conventional and myocardial 2D strain echocardiography before start (T = 0), after 3 months (T = 1), and after 1 year (T = 2), and were compared with 60 healthy age-matched controls. None of the patients showed clinical signs of cardiac failure or abnormal fractional shortening. Cardiac function decreased significantly during treatment and was significantly decreased compared with normal controls. Cardiac troponin T levels were abnormal in 11% of the patients at T = 1 and were significantly related to increased time to global peak systolic longitudinal strain at T = 2 (P = 0.003). N-terminal-pro-brain natriuretic peptide levels were abnormal in 13% of patients at T = 1 and in 20% at T = 2, absolute values increased throughout treatment in 59%. Predictors for abnormal NT-pro-BNP at T = 2 were abnormal NT-pro-BNP at T = 0 and T = 1, for abnormal myocardial 2D strain parameters at T = 2 cumulative anthracycline dose and z-score of the diastolic left ventricular internal diameter at baseline.
Children with newly diagnosed ALL showed decline of systolic and diastolic function during treatment with anthracyclines using cardiac biomarkers and myocardial 2D strain echocardiography. N-terminal-pro-brain natriuretic peptide levels were not related to echocardiographic strain parameters and cTnT was not a predictor for abnormal strain at T = 2.Therefore, the combination of cardiac biomarkers and myocardial 2D strain echocardiography is important in the assessment of cardiac function of children with ALL treated with anthracyclines.
The brain is a specialized immune site representing a unique tumor microenvironment. The availability of fresh brain tumor material for ex vivo analysis is often limited because large parts of many ...brain tumors are resected using ultrasonic aspiration. We analyzed ultrasonic tumor aspirates as a biosource to study immune suppressive mechanisms in 83 human brain tumors. Lymphocyte infiltrates in brain tumor tissues and ultrasonic aspirates were comparable with respect to lymphocyte content and viability. Applying ultrasonic aspirates, we detected massive infiltration of CD4+FoxP3+CD25(high) CD127(low) regulatory T cells (Tregs) in glioblastomas (n = 29) and metastatic brain tumors (n = 20). No Treg accumulation was observed in benign tumors such as meningiomas (n = 10) and pituitary adenomas (n = 5). A significant Treg increase in blood was seen only in patients with metastatic brain tumors. Tregs in high-grade tumors exhibited an activated phenotype as indicated by decreased proliferation and elevated CTLA-4 and FoxP3 expression relative to blood Tregs. Functional analysis showed that the tumor-derived Tregs efficiently suppressed cytokine secretion and proliferation of autologous intratumoral lymphocytes. Most tumor-infiltrating Tregs were localized in close proximity to effector T cells, as visualized by immunohistochemistry. Furthermore, 61% of the malignant brain tumors expressed programmed death ligand-1 (PD-L1), while the inhibitory PD-1 receptor was expressed on CD4+ effector cells present in 26% of tumors. In conclusion, using ultrasonic tumor aspirates as a biosource we identified Tregs and the PD-L1/PD-1 pathway as immune suppressive mechanisms in malignant but not benign human brain tumors.
Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for ...leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. In total, 12 patients with NS developed a malignancy, providing a cumulative risk for developing cancer of 23% (95% confidence interval (CI), 8-38%) up to age 55 years, which represents a 3.5-fold (95% CI, 2.0-5.9) increased risk compared with that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared with that in the general population. Our data do not warrant specific cancer surveillance.
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