Reverse repurposing: Potential utility of cancer drugs in nonmalignant illnesses.

Growth and immune process dysregulation can result in both cancer and nonmalignant disease (hereditary or acquired, with and without predisposition to malignancy). Moreover, perhaps unexpectedly, many nonmalignant illnesses harbor genomic alterations indistinguishable from druggable oncogenic drivers. Therefore, targeted compounds used successfully to treat cancer may have therapeutic potential for nonmalignant conditions harboring the same target. MEK, PI3K/AKT/mTOR, fibroblast growth factor receptor (FGFR), and NRG1/ERBB pathway genes have all been implicated in both cancer and noncancerous conditions, and several cognate antagonists, as well as Bruton's tyrosine kinase inhibitors, JAK inhibitors, and CD20-directed antibodies, have established or theoretical therapeutic potential to bridge cancer and benign diseases. Intriguingly, pharmacologically tractable cancer drivers characterize a wide spectrum of disorders without malignant potential, including but not limited to Alzheimer's disease and a variety of other neurodegenerative conditions, rheumatoid arthritis, achondroplastic dwarfism, and endometriosis. Expanded repositioning of oncology agents in order to benefit benign but serious medical illnesses is warranted.

Real-World Data of Crizanlizumab in Sickle Cell Disease: A Single-Center Analysis.

Background: Crizanlizumab was approved by the United States Food and Drug Administration agency in 2019 for decreasing vaso-occlusive events (VOEs) in sickle cell disease (SCD). Data regarding the use of crizanlizumab in the real-world setting are limited. Our goal was to identify patterns of crizanlizumab prescriptions in our SCD program and evaluate the benefits and identify barriers to its use in our SCD clinic. Methods: We conducted a retrospective analysis of patients who received crizanlizumab at our institution between July 2020 and January 2022. We compared acute care usage patterns before and after initiation of crizanlizumab, adherence to treatment, discontinuation and reasons for discontinuation. High utilizers of hospital-based services were defined as those with more than one visit to the emergency department (ED) per month or more than three visits to the day infusion program per month. Results: Fifteen patients received at least one dose of crizanlizumab 5 mg/kg of actual body weight during the study period. The average number of acute care visits decreased following crizanlizumab initiation but was not statistically significant (20 visits vs. 10 visits, P = 0.07). Among high users of hospital-based services, the average number of acute care visits decreased after initiation of crizanlizumab (40 vs. 16, P = 0.005). Only five patients included in this study remained on crizanlizumab 6 months after initiation. Conclusion: Our study suggests that crizanlizumab use may be helpful in decreasing acute care visits in SCD, particularly among high utilizers of hospital-based acute care services. However, the discontinuation rate in our cohort was extremely high, and further evaluation of efficacy and causes contributing to discontinuation in larger cohorts is warranted.

Evaluation of direct oral anticoagulants versus low molecular weight heparins for venous thromboembolism treatment in patients with gastrointestinal malignancies.

BACKGROUND: Direct oral anticoagulant (DOAC) use in cancer-associated venous thromboembolism (CA-VTE) has increased due to updates in recent guidelines and literature. However, select guidelines caution against DOAC use in patients with gastrointestinal (GI) malignancies due to reported increased bleeding events. The objective of this study was to compare the safety and effectiveness of DOACs versus low-molecular-weight heparins (LMWHs) for CA-VTE treatment in patients with GI malignancies. PATIENTS AND METHODS: This multicenter, retrospective cohort study included patients with primary GI malignancies who received therapeutic anticoagulation with a DOAC or LMWH for CA-VTE between January 1, 2018, and December 31, 2019. The primary outcome was the incidence rate of bleeding events (major, clinically relevant non-major, or minor bleeding events) within a 12-month period following the initiation of therapeutic anticoagulation. The secondary endpoint was the incidence rate of recurrent VTE events within a 12-month period following the start of therapeutic anticoagulation. RESULTS: After screening, 141 patients met inclusion criteria. The incidence rate of all bleeding events significantly differed between DOAC (4.98 events/100 person-months) and LWMH (10.2 events/100 person-months) recipients. The corresponding incidence rate ratio (IRR) with the DOAC group serving as the reference was 2.05 (p = 0.01), with the majority of bleeds in both groups presenting as minor bleeds. No difference was found between the incidence rate of recurrent VTE within a 12-month period of starting therapeutic anticoagulation between groups (IRR 3.08, p = 0.06). CONCLUSION: Our results suggest that DOACs do not pose an additional bleeding risk compared to LMWH in patients with certain GI malignancies. Careful selection of DOAC therapy with respect to bleeding risk is still warranted.

Direct oral anticoagulants or low-molecular-weight heparins for venous thromboembolism in patients with brain tumors.

INTRODUCTION: Patients with central nervous system malignancies have limited representation in studies evaluating DOACs for VTE treatment. This study evaluated the safety and efficacy of DOACs in comparison with LMWH for cancer-associated VTE in patients with primary brain tumors or secondary brain metastases. MATERIALS & METHODS: In this multicenter, retrospective cohort study, adult patients with a diagnosis of primary brain tumor or secondary brain metastases who received either a DOAC or LMWH for treatment of cancer-associated VTE were evaluated. The primary outcome was the cumulative incidence of any intracranial hemorrhage within a 6-month period following the initiation of anticoagulation. Secondary outcomes included the cumulative incidence of any bleeding event, and recurrent VTE events. RESULTS: Between January 1, 2012 and October 9, 2019, one-hundred eleven patients met inclusion criteria. The 6-month cumulative incidence of intracranial hemorrhage was 4.3% (95% CI, 0.74-13.2%) in the DOAC group, compared to 5.9% (95% CI, 1.5-14.9%) in the LMWH group (p = 0.61). The 6-month cumulative incidence of bleeding events was 14.3% (95% CI, 6.2-25.8%) in the DOAC group, compared to 27.8% (95% CI, 15.5-41.6%) in the LMWH group (p = 0.10). The 6-month cumulative incidence of recurrent VTE events was 5.6% in the DOAC group (95% CI, 1.5-14.2%), compared to 6.6% in the LMWH group (95% CI, 1.7-16.5%) (p = 0.96). No differences were found with respect to other secondary outcomes. CONCLUSION: There were no significant differences in bleeding or recurrent VTE events between DOACs and LMWH. These findings suggest DOACs may be safe and effective for VTE treatment in this patient population.

Rebound Vertebral Fractures in a Patient With Lung Cancer After Oncology-Dose Denosumab Discontinuation: A Cautionary Tale.

We describe a 55-year-old woman with lung cancer complicated by bone metastases. Treatment with denosumab (120 mg monthly) was interrupted after 9 doses because of concern for potential osteonecrosis of the jaw during upcoming dental work. Fifteen months after receiving the last dose of denosumab, the patient presented with 7 atraumatic spinal compression fractures requiring kyphoplasty for symptom relief. No malignancy was found in pathology specimens. Evaluation for secondary causes of osteoporosis was negative. This phenomenon of rebound fractures after discontinuing the use of denosumab, an inhibitor of RANK ligand, has been well described in patients with osteoporosis, who receive much lower doses than do patients with cancer. However, this has not been previously reported in oncology patients, likely because most succumb to their disease before denosumab therapy is stopped.

Prophylactic enoxaparin doses may be inadequate in patients undergoing abdominal cancer surgery.

BACKGROUND: The incidence of venous thromboembolism has increased in patients following cancer surgery despite the increased use of prophylactic anticoagulants, suggesting standard doses may be inadequate. We sought to determine the adequacy of enoxaparin prophylaxis in patients undergoing abdominal cancer surgery. METHODS: Peak and trough anti-Xa levels were measured in patients receiving enoxaparin thromboprophylaxis (40 mg daily or 30 mg twice daily, at the surgeon's discretion) after undergoing open abdominal cancer surgery at a single institution. RESULTS: Fifty-five patients received enoxaparin 40 mg daily (group 1), 18 received 30 mg twice daily (group 2; total n = 73). There were no significant differences in gender, age, body mass index, creatinine clearance, diagnosis, or procedure between the two groups. Thirty-nine patients (53.4%) had inadequate peak anti-Xa levels (<0.2 IU/mL) and 69 patients (94.5%) had inadequate trough levels (≤0.1 IU/mL). Group 2 had lower mean peak levels (0.14 ± 0.02 IU/mL) than group 1 (0.22 ± 0.01, P = 0.003), and higher mean trough levels (0.06 ± 0.017) than group 1 (0.02 ± 0.004, P = 0.033). Group 2 had lower incidence of adequate peak anti-Xa levels than group 1 when adjusting for gender, age, body mass index, and preoperative creatinine clearance (OR 0.23, P = 0.039). CONCLUSIONS: The majority of patients had inadequate anti-Xa levels following abdominal cancer surgery, calling into question standard prophylactic enoxaparin dosing.