David J. Reeves

Role of Intrathecal Rituximab and Trastuzumab in the Management of Leptomeningeal Carcinomatosis

Objective: To review evidence for the use of intrathecal rituximab and trastuzumab in the management of leptomeningeal carcinomatosis. Data Sources: A search of MEDLINE (1966–July 2010) and International Pharmaceutical Abstracts (1970–July 2010) was performed using search terms intrathecal, trastuzumab, rituximab, and monoclonal antibody. Additionally, American Society of Clinical Oncology, San Antonio Breast Conference, American Association for Cancer Research, and American Society of Hematology meeting abstracts were searched. Study Selection and Data Extraction: Publications were reviewed for inclusion. Those reporting use of rituximab and trastuzumab intrathecally are reviewed and include 1 Phase 1 trial, 2 small prospective studies, 1 case series, and 15 case reports. Data Synthesis: The treatment of leptomeningeal carcinomatosis is challenging due to the presence of the blood–brain barrier. Numerous systemically administered therapies do not readily penetrate into the site of leptomeningeal disease and have been ineffective. Intrathecal administration of 2 monoclonal antibodies (trastuzumab and rituximab) has been investigated in case reports and case series. Additionally, intrathecal rituximab has been investigated in a Phase 1 study. Survival after intrathecal trastuzumab ranged from 39 days to greater than 72 months and the drug was well tolerated, with no adverse events attributed to it. Doses used in these reports ranged from 5 to 100 mg. Survival after intrathecal rituximab ranged from 1.1 weeks to greater than 3.5 years. In the Phase 1 trial, the maximum tolerated rituximab dose was 25 mg and 60% of patients responded. Four of the 6 responding patients experienced a complete response. Intrathecal rituximab exhibited minor toxicities that resolved quickly without long-term effects. Conclusions: Reports suggest that both trastuzumab and rituximab may be utilized intrathecally. Patients with refractory leptomeningeal carcinomatosis may benefit from a trial of intrathecal trastuzumab or rituximab; however, their use remains investigational, as more data and experience are necessary before intrathecal administration can be considered standard.

Retrospective Evaluation of Methotrexate Elimination when Co-Administered with Proton Pump Inhibitors

AIMS The aim was to assess potential interaction between methotrexate (MTX) and proton pump inhibitors (PPIs) in patients receiving high-dose MTX. METHODS Records of 56 adults receiving 201 cycles of MTX were reviewed to determine effects of PPI administration on MTX elimination. Repeated-measures logistic regressions and Cox regressions were performed to evaluate the possible drug interaction. RESULTS Despite a significant difference between those receiving a PPI and not receiving a PPI in median MTX levels at 24 (8.0 vs. 3.9 μmol l(-1) , respectively, P = 0.013) and 72 h after MTX administration (0.08 vs. 0.05 μmol l(-1) , respectively, P = 0.037), there was no difference between those receiving a PPI and not receiving a PPI in the proportion of patients experiencing delayed elimination at 24 (19.2% vs. 20.2%, respectively, P = 1.000) and 72 h (36.2% vs. 33.7%, respectively, P = 0.765). When data were analysed using Cox regression, controlling for multiple cycles of MTX per patient, PPI use was not a significant predictor of time to MTX < 0.1 μmol l(-1) . When the clustering effect of multiple cycles of MTX per patient was controlled for, co-administration of PPIs was not a significant predictor of MTX level (P = 0.969). A comparison of patients with delayed elimination at any time point and those without delayed elimination indicated that PPI use was not a significant predictor of delayed elimination (P = 0.607). CONCLUSIONS This study does not support previous findings of a significant interaction between PPIs and MTX. Based on these results, the clinical significance of any potential interaction is likely to be small.

Bone Health Management in Prostate Cancer Patients Receiving Androgen Deprivation Therapy

Purpose. Patients receiving androgen deprivation therapy undergo a rapid decline in bone mineral density during the first 6 to 12 months of initiating therapy. The World Health Organization has developed and implemented the Fracture Risk Assessment Tool (FRAX) to predict the ten year risk of a major fracture & hip fracture. Additionally, the National Comprehensive Cancer Network and the National Osteoporosis Foundation have developed osteoporosis guidelines. This study aims to characterize the fracture risk (based on the FRAX tool) and the current management of bone health based on national guidelines compliance. Methods. A retrospective chart review of patients receiving a LHRH agonist at our institution was conducted. Data collection commenced upon Institutional Review Board approval and included demographics, past medical history, medication regimen, history of androgen deprivation therapy, bone health and its management. The ten year fracture risk calculated with the collected information using the FRAX tool. Results. A total of 174 subjects included with a mean age of 65.5 years, 71.8% had stage II prostate cancer, 97.7% received the LHRH agonist leuprolide for a mean of 13.8 ± 18.1 months. In addition to ADT, 57% of patients had ≥ 2 risk factors for developing osteoporosis. The risk of sustaining a major facture increased from 4% to 5.6% after the initiation of ADT (P = <0.001). The risk for sustaining a hip fracture rose from 1.3% to 2.2% (P = <0.001). National guideline compliance was found to be 9%, 5% and 3% respectively for obtaining Dual Energy X-ray Absorptiometry (DEXA) scans, calcium supplementation, and vitamin D supplementation. Conclusion. In addition to predisposing risk factors for osteoporosis, ADT significantly increases the fracture risk in the prostate cancer population. There is room for improvement in the management of bone health as some intervention could have been made in over 90% of patients evaluated.

Methotrexate Elimination When Coadministered With Levetiracetam

Background: Delayed elimination of methotrexate was previously reported in 2 patients receiving concomitant levetiracetam. Objective: To explore the potential interaction between methotrexate and levetiracetam in patients receiving high-dose methotrexate. Methods: This retrospective study reviewed the records of 81 adults receiving 280 cycles of methotrexate to determine the effects of levetiracetam on methotrexate elimination. Institutional review board approval was obtained. Results: Levetiracetam was administered in 33 (12%) cycles of methotrexate. Patients receiving levetiracetam had significantly lower 24-hour methotrexate concentrations compared with those not receiving levetiracetam (2.91 vs 7.37 µmol/L, P = 0.005). Despite this difference, concentrations at 48 and 72 hours were similar between groups. Times to nontoxic methotrexate concentration (<0.1 µmol/L) were the same regardless of the presence of levetiracetam. The frequency of delayed elimination at 24, 48, and 72 hours was similar in both groups as was the frequency of delayed elimination at any time point. Cox regression demonstrated that levetiracetam was not a significant predictor of time to nontoxic methotrexate concentration (P = 0.796; HR = 1.058; 95% CI = 0.692-1.617), and logistic regression demonstrated that levetiracetam was not a significant predictor of delayed elimination at any time point. Levetiracetam use was similar between groups when comparing patients experiencing delayed elimination at any time point with those without delayed elimination (13% vs 10%, respectively, P = 0.527). Conclusion: This study does not support the previous reports of a significant interaction between levetiracetam and methotrexate. A clinically significant interaction is unlikely in those without additional risk factors for delayed elimination.

I.V. ascorbic acid for treatment of apparent rasburicase-induced methemoglobinemia in a patient with acute kidney injury and assumed glucose-6-phosphate dehydrogenase deficiency

PURPOSE A case of apparent rasburicase-induced methemoglobinemia and acute kidney injury treated with i.v. ascorbic acid because of suspected glucose-6-phosphate dehydrogenase (G6PD) deficiency is reported. SUMMARY A 46-year-old African-American man with a recent diagnosis of multiple myeloma and renal insufficiency was admitted to the hospital with a cough, hemoptysis, and fatigue. His medical history included hypertrophic cardiomyopathy, ventricular tachycardia, attention deficit/hyperactivity disorder, and pleural effusion. No treatments for multiple myeloma were started before hospital admission. Levofloxacin 750 mg orally daily for possible pneumonia, lenalidomide 10 mg orally daily, and dexamethasone 20 mg orally weekly were administered. Plasmapheresis was also initiated. Laboratory test results revealed sustained hyperuricemia, which was believed to be due in part to tumor lysis, and a single dose of rasburicase 6 mg i.v. was administered. Subsequently, the patient experienced a decrease in oxygen saturation. Methemoglobinemia was suspected, and the patients methemoglobin fraction was found to be 14.5%. The patient developed worsening shortness of breath and a drop in hemoglobin concentration, consistent with methemoglobinemia and hemolysis. Ascorbic acid 5 g i.v. every 6 hours was initiated for a total of six doses. Because the patient was assumed to have G6PD deficiency, which was later confirmed, methylene blue was avoided. Within 24 hours, the patients oxygen saturation values and symptoms improved. CONCLUSION A patient with apparent rasburicase-induced methemoglobinemia and acute kidney injury was treated with i.v. ascorbic acid (5 g every six hours for six doses) because of the possibility, later proved, that he had G6PD deficiency. The methemoglobinemia resolved without worsening of renal function.

Tolerability of Induction Chemotherapy Dosing Practices in Acute Myeloid Leukemia Patients

For patients with high body surface areas (BSA), differing chemotherapy dosing strategies have been utilized in attempts to reduce toxicity. In a retrospective evaluation, we compared the effects of chemotherapy dosing in acute myeloid leukemia patients with high BSA (>2m(2)) who received capped doses (n=12) to those who received uncapped doses (n=24), and to patients with BSA≤2m(2) (n=42). There were no statistically significant differences among groups (BSA≤2m(2), BSA>2m(2) capped, and BSA>2m(2) uncapped) in the incidences of febrile neutropenia (85.7, 66.7, and 75.0%, respectively, p=0.29), bacteremia (19.0, 8.3, and 16.7%, respectively, p=0.68), mucositis (42.8, 50.0, and 41.7%, respectively, p=0.88) or nausea/vomiting (47.6, 33.3, and 37.5, respectively, p=0.57). Results suggest delivery of unadjusted chemotherapy based on actual body weight is likely safe in hematological malignancies.

Drug-Drug Interaction Between Methotrexate and Levetiracetam Resulting in Delayed Methotrexate Elimination

Objective: To report a case of delayed methotrexate (MTX) elimination while receiving concomitant levetiracetam. Case Report: A 46-year-old man with relapsed osteosarcoma of the base of the skull receiving high-dose MTX tolerated his first cycle of MTX with elimination to nontoxic MTX levels (≤0.1 µmol/L) within 90 hours. After hospital discharge, the patient experienced seizures secondary to brain metastasis and started on levetiracetam, which was continued as maintenance therapy. The patient experienced delayed MTX elimination during cycles 2, 3, and 4 while receiving levetiracetam. On average, elimination to nontoxic MTX levels took 130 hours (106-144 hours). Before the fifth cycle of MTX, lorazepam was substituted for the levetiracetam. MTX was eliminated to nontoxic levels within 95 hours. During all cycles, the patient received standard supportive care and serum creatinine remained stable. No other drugs known to interact with MTX were administered. Discussion: This possible drug interaction has only been reported once in the pediatric population. With a score of 6 on the Drug Interaction Probability Scale for evaluating causation of drug interactions, it is probable that the delayed MTX elimination was caused by an interaction with levetiracetam. Conclusion: Coadministration of levetiracetam and MTX may result in delayed elimination of MTX, increasing the likelihood of toxicity. Consideration should be given to temporarily switching from levetiracetam to another antiepileptic (ie, lorazepam) to prevent this interaction. This is particularly important in those experiencing delayed elimination with prior cycles of concomitant MTX and levetiracetam or those at greater risk for MTX toxicity.

Retrospective Evaluation of Venous Thromboembolism Prophylaxis in the Adult Cancer Population

Study objectives. Hospitalized cancer patients are at an increased risk for venous thromboembolism (VTE) and it is recommended they receive pharmacologic prophylaxis unless otherwise contraindicated. The majority of data supporting this recommendation comes from sub-group analyses and extrapolation of data gathered in general medical/surgical patients. This study seeks to assess the safety and efficacy of VTE prophylaxis in cancer patients admitted to our institution. Methods. Charts of patients 18—89 years of age receiving VTE prophylaxis with unfractionated heparin, low molecular weigh heparin, or fondaparinux while admitted to Karmanos Cancer Center between September and October 2007 were retrospectively reviewed. Risk factors for VTE were assessed and the efficacy/safety of the prophylactic agents was compared. Results. One-hundred and eighty consecutive patients were identified. The average number of risk factors for developing VTE was 3—4 per hospital admission in addition to an active cancer diagnosis. Three VTEs occurred in the heparin group with two patients experiencing a VTE during their admission and one experiencing a VTE within 1 month after discharge. Four (2.6%) patients receiving heparin had a major bleeding event. Minor bleeding occurred in 14.3, 11.5, and 22.2% of patients receiving heparin, enoxaparin, and fondaparinux, respectively. Conclusions. This retrospective study showed cancer patients are at increased risk for VTE, typically with 3—4 risk factors per admission. VTEs were uncommon; however, three patients receiving heparin experienced a VTE and four had a major bleeding event. Minor bleeding rates were similar among groups.

Severe Hypoglycemia Caused by Lenalidomide

Lenalidomide is commonly used for multiple myeloma as either induction or maintenance therapy. The agent is associated with a host of adverse effects, but hypoglycemia has only been reported in one phase I trial in patients with solid tumors. We describe a 74‐year‐old woman who experienced grade 3 hypoglycemia (blood glucose level 35 mg/dl) likely related to lenalidomide. Her medical history was significant for refractory myeloma and type 2 diabetes mellitus. Lenalidomide was started as maintenance therapy following autologous bone marrow transplantation. Approximately 3 years later, she developed refractory hypoglycemia necessitating hospital admission despite stopping antihyperglycemic agents 4 weeks prior to admission. Lenalidomide was withheld during her admission and restarted 2 days prior to discharge. Work‐up for causes of persistent hypoglycemia was negative, and her glucose levels improved over her 26‐day hospitalization. She was readmitted approximately one month later for hypoglycemia, and lenalidomide was permanently discontinued. Again, work‐up for causes of hypoglycemia was negative, and her glucose levels stabilized over her hospitalization. After discontinuation of lenalidomide, hypoglycemia did not recur, and within 1 year the patient required reinitiation of antihyperglycemic medications to control her glucose levels. Given the resolution of hypoglycemia with lenalidomide discontinuation and return of hyperglycemia after restarting the agent, it is likely that lenalidomide was the cause of the patients hypoglycemia. Use of the Naranjo adverse drug reaction probability scale indicated a definite relationship (score of 9) between the patients development of grade 3 hypoglycemia and lenalidomide therapy. Although this adverse drug reaction had been previously reported with lenalidomide during phase I trials in patients with solid tumors, only grade 1 or 2 hypoglycemia was reported in three patients. To our knowledge, this is the first reported case of grade 3 hypoglycemia caused by lenalidomide.

Venous Thromboembolism Prophylaxis Compliance Before and After Electronic Health Record Implementation

Background Adherence to American College of Chest Physicians (CHEST) and National Comprehensive Cancer Network (NCCN) guidelines for venous thromboembolism (VTE) prophylaxis helps avoid thromboembolic complications during hospitalization. Electronic health records (EHR) have the potential to make an impact on guideline adherence, but data are lacking. Objectives To determine compliance with VTE prophylaxis guidelines in internal medicine and oncology populations and to determine whether EHR implementation had any effect on the rate and appropriateness of prophylaxis practices. Methods A retrospective chart review was conducted on medical and oncology patients admitted to the hospital for a 2-month period pre-EHR and post-EHR implementation. Risk assessment tools were available pre and post, however they were not mandatory. The rate of VTE prophylaxis was compared between the 2 time periods, with appropriateness assessed in a subgroup of participants without prophylaxis. Results A total of 2,423 patients on the oncology and internal medicine floors were identified during the pre-EHR (n = 1,171) and post-EHR (n = 1,252) time periods. Patients in the post-EHR group were less likely to be prescribed prophylaxis as compared to those in the pre-EHR group (43% vs 50%; P = .001). In the patients audited for proper prophylaxis use (n = 750), significantly more patients in the post-EHR group had risk factors (84% vs 53%; P <.001) and contraindications (23% vs 8%; P = .001) than in the pre-EHR group. Noncompliance to prophylaxis in patients who were candidates (positive risk factors without contraindications) occurred more often in the post-EHR group (51% vs 39%; P <.001). Conclusion Implementation of an EHR was associated with an increase in the documentation of risk factors and contraindications; however, there was a significant decrease in VTE prophylaxis utilization after EHR implementation.