TP53 mutations are associated with poor outcomes in acute myeloid leukemia (AML). The prognostic impact of mutant TP53 (TP53mut) variant allelic frequency (VAF) is not well established, nor is how this information might guide optimal frontline therapy. We retrospectively analyzed 202 patients with newly diagnosed TP53-mutated AML who underwent first-line therapy with either a cytarabine- or hypomethylating agent (HMA)–based regimen. By multivariate analysis, TP53mut VAF >40% was independently associated with a significantly higher cumulative incidence of relapse (P = .003) and worse relapse-free survival (P = .001) and overall survival (OS; P = .003). The impact of TP53mut VAF on clinical outcomes was driven by patients treated with a cytarabine-based regimen (median OS, 4.7 vs 7.3 months for VAF >40% vs ≤40%; P = .006), whereas VAF did not significantly affect OS in patients treated with HMA. The addition of venetoclax to HMA did not significantly affect OS compared with HMA without venetoclax, both in the entire TP53-mutated population and in patients stratified by TP53mut VAF. Among patients with TP53mut VAF ≤40%, OS was superior in those treated with higher-dose cytarabine, whereas OS was similarly poor for patients with TP53mut VAF >40% regardless of therapy. The best long-term outcomes were observed in those with 1 TP53 mutation with VAF ≤40% who received a frontline cytarabine-based regimen (2-year OS, 38% vs 6% for all others; P < .001). In summary, TP53mut VAF provides important prognostic information that may be considered when selecting frontline therapy for patients with newly diagnosed TP53-mutated AML.

Background: Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown. Methods: We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution. Results: Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2–8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi], 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR. Conclusions: Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP.

Several therapeutic advancements in the treatment of B-cell acute lymphoblastic leukemia (ALL) have surfaced in the past decade, primarily driven by an increased understanding of the immunopathobiology of this disease. The clinical use of blinatumomab, a bispecific antibody that coordinates cytotoxic CD3+ T lymphocytes and CD19+ lymphoblasts, has resulted in improved outcomes in both relapsed/refractory and minimal residual disease-positive B-cell ALL. Promising emerging data also demonstrate the efficacy of this agent in the frontline setting and in combination regimens. Uncertainty remains regarding the optimal sequencing and combination of blinatumomab with cytotoxic chemotherapy and other emerging agents. The pharmacology and clinical data on blinatumomab for adult B-cell ALL, both as monotherapy and in combinations, will be reviewed herein.

Circulating cell-free DNA (ccfDNA) allows for noninvasive peripheral blood sampling of cancer-associated mutations and has established clinical utility in several solid tumors. We performed targeted next-generation sequencing of ccfDNA and bone marrow at the time of diagnosis and after achieving remission in 22 patients with acute myeloid leukemia (AML). Among 28 genes sequenced by both platforms, a total of 39 unique somatic mutations were detected. Five mutations (13%) were detected only in ccfDNA, and 15 (38%) were detected only in bone marrow. Among the 19 mutations detected in both sources, the concordance of variant allelic frequency (VAF) assessment by both methods was high (R2 = 0.849). Mutations detected in only 1 source generally had lower VAF than those detected in both sources, suggesting that either method may miss small subclonal populations. In 3 patients, sequencing of ccfDNA detected new or persistent leukemia-associated mutations during remission that appeared to herald overt relapse. Overall, this study demonstrates that sequencing of ccfDNA in patients with AML can identify clinically relevant mutations not detected in the bone marrow and may play a role in the assessment of measurable residual disease. However, mutations were missed by both ccfDNA and bone marrow analyses, particularly when the VAF was <10%, suggesting that ccfDNA and bone marrow may be complementary in the assessment and monitoring of patients with AML.

Rationale Tyrosine kinase inhibitors are increasingly used in the treatment of cancer. Drug interactions involving tyrosine kinase inhibitors are commonly encountered in clinical practice. The objective of this study was to describe the frequency of tyrosine kinase inhibitor-associated drug interactions among a cohort of oncology patients. Methods Adult patients were included who presented to either of two outpatient oncology practices and were prescribed a tyrosine kinase inhibitor during 2 January 2013 to 1 January 2015. Demographic and medication data were abstracted from electronic medical records. Lexicomp®, Micromedex Solutions®, and medication labeling were utilized to identify potential interactions between tyrosine kinase inhibitors and concomitant medications. Interactions were then assessed by the investigators for clinical significance. The primary outcome was the frequency of significant drug interactions involving tyrosine kinase inhibitors and concomitant medications. Secondary outcomes included describing the nature and clinical impact of interactions, and describing interactions by medication class. Results A total of 356 patients were identified for analysis, in whom 244 potential interactions were identified, and 109 (44.7%) of which were considered severe. Decreased tyrosine kinase inhibitor absorption due to acid suppressive therapy and CYP3A4 interactions were the most frequent mechanisms of potential subtherapeutic and supratherapeutic concentrations, respectively. Potential clinical consequences included QTc prolongation ( n = 53, 48.6%), decreased tyrosine kinase inhibitor concentration ( n = 53, 48.6%), and increased tyrosine kinase inhibitor concentration ( n = 3, 2.8%). Conclusions Safer alternative therapy and/or more frequent clinical monitoring should be considered if an interaction poses a significant risk of increased tyrosine kinase inhibitor toxicity or decreased tyrosine kinase inhibitor efficacy. Oncology pharmacists can play a role in screening for tyrosine kinase inhibitor-associated interactions, recommending alternative therapies or dosing strategies, and monitoring tyrosine kinase inhibitor efficacy and toxicity.

Lacosamide is a new-generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT. We describe a single patient admitted to the study center with status epilepticus and multiorgan failure. The patient required both continuous venovenous hemofiltration (CVVH) and several AEDs. He was receiving intravenous lacosamide 200 mg twice/day at steady state prior to sampling. Plasma lacosamide concentrations were derived using a validated high-performance liquid chromatography method. Parameters were calculated using Phoenix WinNonlin 7.1 software. The peak concentration at steady state was 7.7 mg/L, the trough concentration was 5.9 mg/L (goal 5-12 mg/L). The volume of distribution was 0.7 L/kg, the elimination half-life was 21 hours, and the sieving coefficient was 0.8 (± 0.06). Lacosamide was cleared by CVVH as demonstrated by the sieving coefficient, but plasma concentrations remained within goal range throughout the dosing interval. These results may suggest that lacosamide 200 mg twice/day is a useful dosing strategy for critically ill patients who require CVVH.

Direct to consumer advertising (DTCA) of prescription drugs has increased dramatically in the past two decades. The effect of this increase in advertising on the frequency of inappropriate prescribing is poorly understood, as are the factors that may underly inappropriate prescribing. A review of existing observational and experimental studies that address advertising-related prescription requests and contain some measure of prescription appropriateness demonstrate that DTCA increases prescription requests, increases the likelihood of prescription, and increases both appropriate and inappropriate prescribing. Patient expectations, insufficient information sharing, and patient satisfaction surveys are proposed contributors to potentially inappropriate prescribing in response to DTCA.

When used adjunctively to blood product transfusion in actively bleeding patients, use of adjusted body weight-based desmopressin did not negatively affect clinical outcomes. More data are needed to confirm this dosing strategy.