Mediport use as an acceptable standard for CAR T cell infusion.

Introduction: Mediport use as a clinical option for the administration of chimeric antigen receptor T cell (CAR T cell) therapy in patients with B-cell malignancies has yet to be standardized. Concern for mediport dislodgement, cell infiltration, and ineffective therapy delivery to systemic circulation has resulted in variable practice with intravenous administration of CAR T cell therapy. With CAR T cell commercialization, it is important to establish practice standards for CAR T cell delivery. We conducted a study to establish usage patterns of mediports in the clinical setting and provide a standard of care recommendation for mediport use as an acceptable form of access for CAR T cell infusions. Methods: In this retrospective cohort study, data on mediport use and infiltration rate was collected from a survey across 34 medical centers in the Pediatric Real-World CAR Consortium, capturing 504 CAR T cell infusion routes across 489 patients. Data represents the largest, and to our knowledge sole, report on clinical CAR T cell infusion practice patterns since FDA approval and CAR T cell commercialization in 2017. Results: Across 34 sites, all reported tunneled central venous catheters, including Broviac® and Hickman® catheters, as accepted standard venous options for CAR T cell infusion. Use of mediports as a standard clinical practice was reported in 29 of 34 sites (85%). Of 489 evaluable patients with reported route of CAR T cell infusion, 184 patients were infused using mediports, with no reported incidences of CAR T cell infiltration. Discussion/Conclusion: Based on current clinical practice, mediports are a commonly utilized form of access for CAR T cell therapy administration. These findings support the safe practice of mediport usage as an accepted standard line option for CAR T cell infusion.

Prospective assessment of risk biomarkers of sinusoidal obstruction syndrome after hematopoietic cell transplantation.

BACKGROUNDCurrently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using 3 proteins: L-ficolin, hyaluronic acid (HA), and stimulation 2 (ST2). METHODSBetween 2017 and 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence on day 35 after HCT, and overall survival (OS) on day 100 after HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort.RESULTSCombination of the 3 biomarkers measured on day 3 after HCT in the prospective cohort provided 80% (95% CI 55%-100%) sensitivity and 73% (95% CI 62%-83%) specificity for risk of SOS occurrence. Patients with low L-ficolin were 9 times (95% CI 3-32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95% CI 1.9-22.0) and 5.5 (95% CI 2.3-13.1) times more likely to develop SOS. These 3 markers also predicted worse day 100 OS - L-ficolin: HR, 10.0 (95% CI 2.2-45.1), P = 0.0002; HA: HR, 4.1 (95% CI 1.0-16.4), P = 0.031; and ST2: HR, 3.9 (95% CI 0.9-16.4), P = 0.04.CONCLUSIONL-ficolin, HA, and ST2 levels measured as early as 3 days after HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT03132337.FUNDINGNIH.

Outcomes of pediatric patients with therapy-related myeloid neoplasms.

Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.

Simultaneous quantification of vincristine and its major M1 metabolite from dried blood spot samples of Kenyan pediatric cancer patients by UPLC-MS/MS.

Vincristine (VCR) is an integral part of chemotherapy regimens in the US and in developing countries. There is a paucity of information about its disposition and optimal therapeutic dosing. VCR is preferentially metabolized to its major M1 metabolite by the polymorphic CYP3A5 enzyme, which may be clinically significant as CYP3A5 expression varies across populations. Thus, it is important to monitor both VCR and M1 and characterize their dispositions. A previously developed HPLC-MS/MS method for VCR quantification was not sensitive enough to quantify the M1 metabolite beyond 1 h post VCR dose (not published). Establishing a highly sensitive assay is a pre-requisite to simultaneously quantify and monitor VCR and M1, which will enable characterization of drug exposure and dispositions of both analytes in a pediatric cancer population. The addition of formic acid during the extraction process enhanced M1 extraction from DBS samples. A sensitive, accurate, and precise UPLC-MS/MS assay method for the simultaneous quantification of VCR and M1 from human dried blood spots (DBS) was developed and validated. Chromatographic separation was performed on Inertsil ODS-3 C18 column (5 µm, 3.0 × 150 mm). A gradient elution of mobile phase A (methanol-0.2 % formic acid in water, 20:80 v/v) and mobile phase B (methanol-0.2 % formic acid in water, 80:20 v/v) was used with a flow rate of 0.4 mL/min and a total run time of 5 min. The analytes were ionized by electrospray ionization in the positive ion mode. The linearity range for both analytes in DBS were 0.6-100 ng/mL for VCR and 0.4-100 ng/mL for M1. The intra- and inter-day accuracies for VCR and M1 were 93.10-117.17 % and 95.88-111.21 %, respectively. While their intra- and inter-day precisions were 1.05-10.11 % and 5.78-8.91 %, respectively. The extraction recovery of VCR from DBS paper was 35.3-39.4 % and 10.4-13.4 % for M1, with no carryover observed for both analytes. This is the first analytical method to report the simultaneous quantification of VCR and M1 from human DBS. For the first time, concentrations of M1 from DBS patient samples were obtained beyond 1 h post VCR dose. The developed method was successfully employed to monitor both compounds and perform pharmacokinetic analysis in a population of Kenyan pediatric cancer patients.

A Metabolomics Approach for Early Prediction of Vincristine-Induced Peripheral Neuropathy.

Vincristine is a core chemotherapeutic drug administered to pediatric acute lymphoblastic leukemia patients. Despite its efficacy in treating leukemia, it can lead to severe peripheral neuropathy in a subgroup of the patients. Peripheral neuropathy is a debilitating and painful side-effect that can severely impact an individual's quality of life. Currently, there are no established predictors of peripheral neuropathy incidence during the early stage of chemotherapeutic treatment. As a result, patients who are not susceptible to peripheral neuropathy may receive sub-therapeutic treatment due to an empirical upper cap on the dose, while others may experience severe neuropathy at the same dose. Contrary to previous genomics based approaches, we employed a metabolomics approach to identify small sets of metabolites that can be used to predict a patient's susceptibility to peripheral neuropathy at different time points during the treatment. Using those identified metabolites, we developed a novel strategy to predict peripheral neuropathy and subsequently adjust the vincristine dose accordingly. In accordance with this novel strategy, we created a free user-friendly tool, VIPNp, for physicians to easily implement our prediction strategy. Our results showed that focusing on metabolites, which encompasses both genotypic and phenotypic variations, can enable early prediction of peripheral neuropathy in pediatric leukemia patients.

Successful Allogeneic Stem Cell Transplant in Pediatric Patients With Diminished Left Ventricular Ejection Fractions.

Chemotherapy-associated cardiotoxicity may delay or impair the ability to administer fully myeloablative chemotherapy for stem cell transplant in those with reduced left ventricular ejection fraction. Studies in adults have been inconsistent regarding the value of ejection fraction in predicting cardiotoxicity in the posttransplant period. Recent publications, however, have demonstrated successful stem cell transplantation in adults despite low ejection fractions. This case series highlights 2 pediatric patients who were successfully treated with stem cell transplantation without posttransplant cardiac complications, despite pretransplant ejection fractions of 38% and 29%.

Chaplain care in pediatric oncology: Insight for interprofessional collaboration.

BACKGROUND: Although attending to spiritual and religious needs is part of high quality care of pediatric cancer patients, oncology clinicians may not understand the role of the chaplain, resulting in underutilization of resources and failure to fully integrate the chaplain into the clinical team. We provide a description of what the chaplain does in the care of pediatric oncology patients. METHODS: We conducted a qualitative content analysis of chaplain chart notes over a one-year period on the pediatric oncology service at a freestanding children's hospital. Using criteria designed to capture multiple potential factors in chaplain referral, we selected 30 patients for thematic analysis. RESULTS: In 2016, 166 pediatric patients were diagnosed with cancer and received ongoing care at our institution. From the 30 patients selected, 230 chaplain encounters were documented in the medical chart. Three major themes emerged. (1) The chaplains provided a rich description of spiritual and psychosocial aspects of the patient and family's experience; (2) chaplains provided diverse interventions, both religious and secular in nature; and (3) chaplains provided care within a longitudinal relationship. All three themes depend on the empathic listening by a chaplain. CONCLUSIONS: The chaplains' observations about patient and family beliefs, experiences, and emotional/spiritual states have the potential to inform the interdisciplinary care of the patient. Chaplain documentation provides insight into how spiritual care interventions and close relationships may promote patient and family well-being. In future work, we will explore how to give voice to their insights in caring for pediatric oncology patients.

Genetic Variants Associated With Vincristine-Induced Peripheral Neuropathy in Two Populations of Children With Acute Lymphoblastic Leukemia.

Vincristine is one of the core chemotherapy agents used in the treatment of pediatric acute lymphoblastic leukemia (ALL). However, one of the major toxicities resulting from vincristine exposure is vincristine-induced peripheral neuropathy (VIPN). When VIPN results in significant morbidity, the vincristine dose may need to be reduced, thus potentially decreasing the effectiveness of treatment. To date, there are no robust biomarkers used clinically to determine which patients will be at risk for worse neuropathy. The current study included genomewide association study (GWAS) in two independent cohorts: Pediatric Oncology Group (POG) ALL trials and a multicenter study based at Indiana University in children with ALL. A meta-analysis of the cohorts identified two single-nucleotide polymorphisms (SNPs), rs1045644 and rs7963521, as being significantly (P value threshold 0.05/4749 = 1.05E-05) associated with neuropathy. Subsequently these SNPs may be effective biomarkers of VIPN in children with ALL.

The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond.

Once unimaginable, fertility management is now a nationally established part of cancer care in institutions, from academic centers to community hospitals to private practices. Over the last two decades, advances in medicine and reproductive science have made it possible for men, women and children to be connected with an oncofertility specialist or offered fertility preservation soon after a cancer diagnosis. The Oncofertility Consortium's National Physicians Cooperative is a large-scale effort to engage physicians across disciplines - oncology, urology, obstetrics and gynecology, reproductive endocrinology, and behavioral health - in clinical and research activities to enable significant progress in providing fertility preservation options to children and adults. Here, we review the structure and function of the National Physicians Cooperative and identify next steps.

CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer.

BACKGROUND: Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians. PROCEDURE: Kenyan children with cancer who were undergoing treatment including VCR were recruited for a prospective cohort study. Patients received IV VCR 2 mg/m2 /dose with a maximum dose of 2.5 mg as part of standard treatment protocols. VCR pharmacokinetics (PK) sampling was collected via dried blood spot cards and genotyping was conducted for common functional variants in CYP3A5, multi-drug resistance 1 (MDR1), and microtubule-associated protein tau (MAPT). VIPN was assessed using five neuropathy tools. RESULTS: The majority of subjects (91%) were CYP3A5 high-expresser genotype. CYP3A5 low-expresser genotype subjects had a significantly higher dose and body surface area normalized area under the curve than CYP3A5 high-expresser genotype subjects (0.28 ± 0.15 hr·m2 /l vs. 0.15 ± 0.011 hr·m2 /l, P = 0.027). Regardless of which assessment tool was utilized, minimal neuropathy was detected in this cohort. There was no difference in the presence or severity of neuropathy assessed between CYP3A5 high- and low-expresser genotype groups. CONCLUSION: Genetic factors are associated with VCR PK. Due to the minimal neuropathy observed in this cohort, there was no demonstrable association between genetic factors or VCR PK with development of VIPN. Further studies are needed to determine the role of genetic factors in optimizing dosing of VCR for maximal benefit.

Low serum albumin levels prior to pediatric allogeneic HCT are associated with increased need for critical care interventions and increased 6-month mortality.

Poor nutritional status in HCT patients is a negative prognostic factor. There are no pediatric studies evaluating albumin levels prior to HCT and need for critical care interventions. We hypothesized that pediatric patients with low albumin levels, routinely measured 30 days (±10 days) prior to allogeneic HCT, have a higher risk of critical care interventions in the post-transplant period. We performed a 5-year retrospective study of pediatric patients who underwent allogeneic HCT for any indication. Patients were categorized based on albumin level. Hypoalbuminemia was defined as <3.1 g/dL. A total of 73 patients were included, with a median age of 7.4 years (IQR 3.3, 13.2). Patients with hypoalbuminemia had higher needs for critical care interventions including non-invasive ventilation (44% vs 8%, P=.01), mechanical ventilation (67% vs 17%, P<.01), and vasoactive therapy (56% vs 16%, P=.01). Patients with hypoalbuminemia also had a higher 6-month mortality (56% vs 17%, P=.02). Our data demonstrate that children undergoing allogeneic HCT with hypoalbuminemia in the pretransplant period are more likely to require critical care interventions and have higher 6-month mortality. These findings identify an at-risk population in which nutritional improvements may be instituted prior to HCT in hopes of improving outcomes.