Utilization of supportive care medications and opportunities for pre-emptive pharmacogenomic testing in pediatric and young adults with leukemia.

This study aimed to evaluate the utilization of drugs with pharmacogenomic guidelines (PGx-drugs) for personalized dosing in pediatric leukemia. A retrospective observational study of pediatric leukemia patients admitted between 2009-2019 at a single-center academic children's hospital was conducted to determine PGx-drug exposure within 3 years of diagnosis. Along with baseline demographic and clinical characteristics of these patients, data regarding dates of diagnosis, relapse, death were collected. During the study period, inclusion criteria were met by 714 patients. The most frequently given medications were ondansetron (96.1%), morphine (92.2%), and allopurinol (85.3%) during the study period. In this cohort, 82% of patients received five or more PGx-drugs. Patients diagnosed with acute myeloid leukemia and leukemia unspecified were prescribed more PGx-drugs than other types of leukemia. There was a significant relationship between age at diagnosis and the number of PGx-drugs prescribed. Adolescents and adults both received a median of 10 PGx-drugs, children received a median of 6 PGx-drugs, and infants received a median of 7 PGx-drugs (p < 0.001). Patients with recurrent leukemia had significantly more PGx-drugs prescribed compared to those without recurrent disease, 10 drugs and 6 drugs, respectively (p < 0.001). Patients diagnosed with childhood leukemia are high utilizers of PGx-drugs. There is a vital need to understand how PGx testing may be utilized to optimize treatment and enhance quality of life. Preemptive PGx testing is a tool that aids in optimization of drug therapy and decreases the need for later treatment modifications. This can result in financial savings from decreased health-care encounters.

ZMIZ1::ABL1 Fusion: An Uncommon Molecular Event With Clinical Implications in Pediatric Cancer.

CONTEXT.­: Pediatric B-cell acute lymphoblastic leukemia is genetically and phenotypically heterogeneous, with a genetic landscape including chromosomal translocations that disrupt ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1). OBJECTIVE.­: To characterize an uncommon chromosomal translocation in acute leukemia. DESIGN.­: Genetic testing, including karyotype and fluorescence in situ hybridization (FISH) analysis, was used to determine the underlying genetic aberration driving the disorder and to guide disease classification and risk stratification. More-detailed testing using RNA sequencing was performed, based on the results from these assays. Three-dimensional molecular modeling was used to visualize the impact of aberrant fused transcripts identified by transcriptome profiling. RESULTS.­: Karyotype analysis of the bone marrow demonstrated a complex karyotype with, most notably, a t(9;10)(q34.1;q22) translocation. ABL1 break-apart probe FISH findings supported ABL1 disruption. Bone marrow transcriptome analysis revealed mutant ZMIZ1::ABL1 (ZMIZ1, zinc finger MIZ-type containing 1) fusion transcripts as a consequence of t(9;10)(q34.1;q22). Three-dimensional modeling of the mutant ZMIZ1::ABL1 fusion protein confirmed an altered ABL1 protein structure compared to that of the wild type, suggesting a constitutively active conformation. CONCLUSIONS.­: The t(9;10) translocation resulting in ZMIZ1::ABL1 fusion transcripts is an uncommon form of BCR::ABL1-like (BCR, BCR activator of RhoGEF and GTPase) acute lymphoblastic leukemia. Although the karyotype was complex, identifying the t(9;10)(q34.1;q22) translocation, ABL1 disruption, and ZMIZ1::ABL1 transcript enabled effective ABL1-targeted treatment. Our data support the use of tyrosine kinase inhibitors to treat ZMIZ1::ABL1-derived B-cell acute lymphoblastic leukemia.

Treatment practices and response in kaposiform hemangioendothelioma: A multicenter cohort study.

BACKGROUND AND OBJECTIVES: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials. METHODS: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. RESULTS: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. CONCLUSIONS: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.

Effect of SLCO1B1 Polymorphisms on High-Dose Methotrexate Clearance in Children and Young Adults With Leukemia and Lymphoblastic Lymphoma.

High-dose (HD) methotrexate (MTX) is a critical component of treatment for hematologic malignancies in children and young adults. Therapeutic drug monitoring is necessary due to substantial interindividual variation in MTX clearance. Common function-altering polymorphisms in SLCO1B1 (encodes OATP1B1, which transports MTX) may contribute to clearance variability. We performed pharmacokinetic modeling using data for 106 children and young adults treated with HD MTX for hematologic malignancies; of 396 total courses of HD MTX, 360 consisted of 5 g/m2 over 24 hours. We evaluated the contribution of clinical covariates and SLCO1B1 genotype (388A>G and 521T>C) to MTX clearance variability. Of the clinical covariates studied, patient weight improved the pharmacokinetic model most significantly (P < 0.001). The addition of the SLCO1B1 variants individually further improved the model (P < 0.05 for each). An interaction between these variants was suggested when both were included (P = 0.017). SLCO1B1 genotype should be considered in efforts to personalize HD MTX dosing.

Organic Anion Transporting Polypeptides: Emerging Roles in Cancer Pharmacology.

The organic anion transporting polypeptides (OATPs) are a superfamily of drug transporters involved in the uptake and disposition of a wide array of structurally divergent endogenous and exogenous substrates, including steroid hormones, bile acids, and commonly used drugs, such as anti-infectives, antihypertensives, and cholesterol lowering agents. In the past decade, OATPs, primarily OATP1A2, OATP1B1, and OATP1B3, have emerged as potential mediators of chemotherapy disposition, including drugs such as methotrexate, doxorubicin, paclitaxel, docetaxel, irinotecan and its important metabolite 7-ethyl-10-hydroxycamptothecin, and certain tyrosine kinase inhibitors. Furthermore, OATP family members are polymorphic and numerous studies have shown OATP variants to have differential uptake, disposition, and/or pharmacokinetics of numerous drug substrates with important implications for interindividual differences in efficacy and toxicity. Additionally, certain OATPs have been found to be overexpressed in a variety of human solid tumors, including breast, liver, colon, pancreatic, and ovarian cancers, suggesting potential roles for OATPs in tumor development and progression and as novel targets for cancer therapy. This review focuses on the emerging roles for selected OATPs in cancer pharmacology, including preclinical and clinical studies suggesting roles in chemotherapy disposition, the pharmacogenetics of OATPs in cancer therapy, and OATP overexpression in various tumor tissues with implications for OATPs as therapeutic targets.

Levocarnitine for asparaginase-induced hepatic injury: a multi-institutional case series and review of the literature.

Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially ameliorate the mitochondrial toxicity of asparaginase. In this retrospective case series, we describe the clinical presentation and management of six pediatric and young adult patients (mean age 12.7, range 9-24 years) with ALL who developed Grade 3-4 hyperbilirubinemia following administration of asparaginase as part of induction/re-induction therapy. Five of these patients were treated with levocarnitine with subsequent improvement of hyperbilirubinemia, while one patient was given levocarnitine prophylactically during induction and developed Grade 3 hyperbilirubinemia, but did not require therapy adjustments or delays. Increased awareness in the pediatric oncology community regarding asparaginase-associated hepatic toxicity and the potential role of levocarnitine in management is warranted.

Cytosolic phospholipase A2 as a molecular target for the radiosensitization of ovarian cancer.

In ovarian cancer, the molecular targeted chemotherapeutics could increase the efficiency of low-dose radiotherapy while decreasing injury to adjusted organs. In irradiated A2780 human ovarian carcinoma cells, cytosolic phospholipase A2 (cPLA(2)) inhibitor AACOCF(3) prevented activation of pro-survival Akt signaling and enhanced cell death. The potential molecular mechanisms of this effect could involve signaling through lysophosphatidic acid receptors. In the heterotopic A2780 tumor model using nude mice, cPLA(2) inhibition significantly delayed tumor growth compared to treatment with radiation or vehicle alone. These results identify cPLA(2) as a molecular target to enhance the therapeutic ratio of radiation in ovarian cancer.