Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers.

BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

Impact of coronavirus of 2019 on the delivery of pharmacy services to patients with cancer: An international survey of oncology pharmacy practitioners.

INTRODUCTION: The coronavirus of 2019 pandemic has necessitated vast and rapid changes in the way oncology pharmacy services are delivered around the world. METHODS/AIMS: An international survey of oncology pharmacists and technicians was conducted via the International Society of Oncology Pharmacy Practitioners and collaborating global pharmacy organisations to determine the impact that the coronavirus of 2019 has had on pharmacy service delivery, pharmacy practitioners and oncology practice. RESULTS: The survey received 862 responses from 40 different countries from September to October 2020. The majority of respondents were pharmacists (n = 841, 97.6%), with 24% involved in the direct care of patients with the coronavirus of 2019. Of the survey participants, 55% increased their time working remotely, with remote activities including dispensing, patient assessment/follow-up and attending multi-disciplinary rounds. Respondents reported a 72% increase in the use of technology to perform remote patient interaction activities and that participation in educational meetings and quality improvement projects was reduced by 68% and 44%, respectively. Workforce impacts included altered working hours (50%), cancelled leave (48%) and forced leave/furloughing (30%). During the pandemic, respondents reported reduced access to intensive care (19%) and anti-cancer (15%) medications. In addition, 39% of respondents reported reduced access to personal protective equipment, including N95 masks for chemotherapy compounding. Almost half of respondents (49%) reported that cancer treatments were delayed or intervals were altered for patients being treated with curative intent. A third of practitioners (30%) believed that patient outcomes would be adversely impacted by changes to pharmacy services. Sixty-five percent of respondents reported impacts on their mental health, with 12% utilising support services. CONCLUSION: The coronavirus of 2019 pandemic has altered the way oncology pharmacy services are delivered. These results demonstrate the adaptability of the oncology pharmacy profession and highlight the importance of formal evaluation of the varied practice models to determine the evidence-based practices that enhance pharmacy services and, thus, should be reinstated as soon as practical and reasonable.

Outpatient clinical pharmacy practice in the face of COVID-19 at a cancer center in New York City.

PURPOSE: With the rapid spread of COVID-19 in New York City since early March 2020, innovative measures were needed for clinical pharmacy specialists to provide direct clinical care safely to cancer patients. Allocating the workforce was necessary to meet the surging needs of the inpatient services due to the COVID-19 outbreak, which had the potential to compromise outpatient services. We present here our approach of restructuring clinical pharmacy services and providing direct patient care in outpatient clinics during the pandemic. DATA SOURCES: We conducted a retrospective review of electronic clinical documentation involving clinical pharmacy specialist patient encounters in 9 outpatient clinics from March 1, 2020 to May 31, 2020. The analysis of the clinical pharmacy specialist interventions and the impact of the interventions was descriptive. DATA SUMMARY: As hospital services were modified to handle the surge due to COVID-19, select clinical pharmacy specialists were redeployed from the outpatient clinics or research blocks to COVID-19 inpatient teams. During these 3 months, clinical pharmacy specialists were involved in 2535 patient visits from 9 outpatient clinics and contributed a total of 4022 interventions, the majority of which utilized telemedicine. The interventions provided critical clinical pharmacy care during the pandemic and omitted 199 in-person visits for medical care. CONCLUSION: The swift transition to telemedicine allowed the provision of direct clinical pharmacy services to patients with cancer during the COVID-19 pandemic.

Correlation of IL-6 secretion and hyponatremia with the use of CD19+ chimeric antigen receptor T-cells
.

BACKGROUND: Various studies have demonstrated that interleukin-6 (IL-6) activates the central magnocellular arginine vasopressin (AVP)-secreting neurons in the brain to produce non-osmotic, non-volume-mediated increases in AVP. The most common toxicity of CD19+ chimeric antigen receptor (CAR) T-cells is cytokine release syndrome, which is related to increased levels of IL-6. This study will evaluate the correlation of IL-6 levels with hyponatremia in patients receiving CD19+ CAR T-cells. MATERIALS AND METHODS: This is a single-center retrospective analysis of adult patients who received CD19+ CAR T-cells for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). RESULTS: Hyponatremia, defined as a serum sodium (Na) ≤ 135 mEq/L, occurred in 31 (61%) patients. A change in Na > 7 mEq occurred in 32 (63%) patients, and the median lowest Na was 133 mEq/L (interquartile range (IQR): 131 - 136)). There was an inverse linear relationship between IL-6 levels and lowest Na (p = 0.001). Overall, per 10-fold increase in IL-6, Na decreased by an average of 2.68 mEq/L. CONCLUSION: Hyponatremia is common in patients who received CD19+ CAR T-cells. There is an inverse linear relationship between IL-6 levels and nadir Na (p = 0.001). Further studies will be needed to confirm a causative relationship between IL-6 levels and hyponatremia following CD19+ CAR T-cell infusion.

The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia.

OBJECTIVE: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). DATA SOURCES: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR). STUDY SELECTION/DATA EXTRACTION: Studies of pharmacology, clinical efficacy, and safety of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified. DATA SYNTHESIS: Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90% in pediatrics, but it remains suboptimal in adult patients. As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL. In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL. CONCLUSION: Outcomes of patients with relapsed disease are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells. Although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial. The optimal sequencing of these therapies still remains a question.

Hypoalbuminemia is significantly associated with increased clearance time of high dose methotrexate in patients being treated for lymphoma or leukemia.

As a weak acid, methotrexate (MTX) is bound to serum albumin and has variable protein binding. The purpose of this study was to assess serum albumin's relationship with MTX pharmacokinetics by comparing MTX clearance and toxicities between patients with normal serum albumin to those with hypoalbuminemia. This single-center retrospective study included adult patients with leukemia or lymphoma who received their first MTX at a dose ≥1 g/m2. Hypoalbuminemia was defined as serum albumin ≤3.4 g/dL. MTX clearance was defined as the first documented time the MTX level ≤0.05 µM. Fisher's exact tests and Wilcoxon rank sum tests were used to examine differences in toxicities, and Cox proportional hazard regression was used to assess relationship with time to clearance. Of 523 patients identified, 167 patients were evaluable. One hundred thirty-five patients had normal serum albumin and 32 had hypoalbuminemia. Hypoalbuminemia was associated with a higher proportion of patients experiencing edema, ascites or pleural effusions (34 vs. 12 %, p = 0.006), and the concomitant use of nephrotoxic agents (41 vs. 20 %, p = 0.021). Hypoalbuminemia was associated with a significantly longer time to MTX clearance (median 96 vs. 72 h, p = 0.004). In addition, patients with hypoalbuminemia had a higher proportion of hyperbilirubinemia and significantly longer hospitalization (median 14 vs. 5 days, p < 0.001). In conclusion, hypoalbuminemia was associated with increased time to MTX clearance and increased length of hospitalization. High dose MTX is safe to administer in patients with low albumin levels, with appropriate leucovorin rescue, and good supportive care.

Blinatumomab: A First-in-Class Bispecific T-Cell Engager for Precursor B-Cell Acute Lymphoblastic Leukemia.

OBJECTIVE: To review the clinical pharmacology, efficacy, and safety of blinatumomab for the treatment of pediatric and adult precursor B-cell acute lymphoblastic leukemia (B-ALL). DATA SOURCES: A literature search of EMBASE (1947 to April 2015), Medline (1946 to April 2015), PubMed (1996 to April 2015), the U.S. National Institutes of Health Clinicaltrials.gov, the Food and Drug Administration, and relevant meeting abstracts was conducted using the terms blinatumomab, BiTE, bispecific T-cell engager, MT103, MEDI-538, and Blincyto. STUDY SELECTION/DATA EXTRACTION: Human and animal studies describing the pharmacology, pharmacokinetics and pharmacodynamics, efficacy, and safety of blinatumomab for precursor B-ALL were identified. DATA SYNTHESIS: Blinatumomab is a first-in-class bispecific T-cell engager (BiTE) antibody derived from a B-lineage specific antitumor mouse monoclonal antibody that binds to both CD19 of B-cells and CD3 of T-cells. A pivotal phase II trial demonstrated that response rates were high in a refractory or relapsed patient population, with 43% achieving complete remission (CR). Median relapse-free survival was 5.9 months for those with CR or CR with incomplete hematological recovery. Median overall survival was 6.1 months, and 60% of patients achieved minimal residual disease (MRD) negativity. The most common adverse events included pyrexia, neurological events, headache, febrile neutropenia, peripheral edema, nausea, hypokalemia, constipation, and anemia. CONCLUSIONS: Blinatumomab is a novel BiTE therapeutic monoclonal antibody that has shown promising results in patients with relapsed or refractory ALL or those achieving a CR with persistent MRD. Phase III clinical trials should define the optimal place in therapy of blinatumomab.

Rates of Renal Toxicity in Cancer Patients Receiving Cisplatin With and Without Mannitol.

BACKGROUND: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of mannitol as a nephroprotectant in combination with hydration. OBJECTIVE: We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in cancer patients receiving single-agent cisplatin with and without mannitol. METHODS: This single-center retrospective analysis was a quasi experiment created by the national mannitol shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). RESULTS: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive mannitol were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m2 dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. CONCLUSIONS: When limited quantities of mannitol are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m2 cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of mannitol.

The role of mannitol as a nephroprotectant in patients receiving cisplatin therapy.

OBJECTIVE: To review the efficacy and safety of concomitant mannitol administration with cisplatin therapy to reduce the incidence of nephrotoxicity. DATA SOURCES: A literature search was performed via MEDLINE, PubMed, and the Cochrane Library (1945-August 2011) using the terms mannitol, cisplatin, nephrotoxicity, and forced diuresis. Reference citations from the publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: The search was limited to studies conducted in humans. All studies in which mannitol was used for forced diuresis with cisplatin therapy were evaluated. DATA SYNTHESIS: Cisplatin therapy can lead to transient and permanent renal impairment. Molecular and histologic changes occur in the renal tubules, which contribute to nephrotoxicity. The adverse effect profile of cisplatin is well documented, but the prevention strategies to alleviate renal impairment due to treatment are less understood. Mannitol plus hydration has been used for several years to alleviate toxicity associated with cisplatin therapy. However, the data for mannitol administration have not been convincing. When the use of mannitol and hydration is compared directly to hydration alone, mannitol shows no benefit. In some patients, not only was mannitol not protective, its administration was associated with worsening renal function. CONCLUSIONS: Although mannitol plus hydration is used to decrease cisplatin-induced nephrotoxicity, there are no compelling data that the addition of mannitol is more nephroprotective than the use of hydration alone. Appropriate hydration remains the most reasonable strategy to reduce the incidence of cisplatin-induced nephrotoxicity.

National Survey on the Effect of Oncology Drug Shortages in Clinical Practice: A Hematology Oncology Pharmacy Association Survey.

PURPOSE: Drug shortages are a clear and growing challenge. Prominent shortages included oncology medications and supportive care products essential for the care of patients with cancer. Oncology drug shortages often result in disruptions in the timing of chemotherapy treatments, alterations in the dose or regimen administered, or even missed doses when alternative agents are unavailable. The purpose of this survey was to characterize the impact of oncology drug shortages across the United States, including the experiences of health care organizations, resource implications, and the impact on patient safety, patient care, and clinical trials. METHODS: A 36-item online survey was distributed to membership of the Hematology/Oncology Pharmacy Association to gather information on shortages of oncology drugs (ie, all drugs essential in the care of patients with cancer, including supportive care agents). RESULTS: Sixty-eight US organizations participated in the survey between December 2019 and July 2020. Sixty-three percent of institutions reported one or more drug shortages per month, with a 34% increase in 2019 from 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents. The most difficult agents to obtain were vincristine, vinblastine, intravenous immunoglobulin, leucovorin, and Bacillus Calmette-Guerin. CONCLUSION: A survey of US oncology pharmacists indicated that oncology drug shortages occurred frequently in 2020. Shortages led to delays in chemotherapy and changes in treatment or omission, complicated clinical research, and increased risk of medication errors and adverse outcomes.

Phase I trial of vinflunine and pemetrexed in refractory solid tumors.

BACKGROUND: Vinflunine is a novel vinca alkaloid with promising single agent clinical activity. Pemetrexed has at least additive activity with other vincas. A phase I trial was undertaken to assess the safety of vinflunine and pemetrexed in patients with refractory solid tumors. METHODS: A standard 3-patient cohort dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the vinflunine/pemetrexed combination. Pemetrexed 500 mg/m(2) was given with vinflunine 280 mg/m(2) (cohort 1), 300 mg/m(2) (cohort 2) or 320 mg/m(2) (cohort 3) on day 1 of a 21-day cycle. RESULTS: 19 patients were enrolled, median age 58 years (range 32 to 77) and had a median of 3 (range 1-6) prior therapies. DLT occurred 1 of 6 pts in cohort 1 (thrombocytopenia, hyponatremia), 2 of 10 pts in cohort 2 (febrile neutropenia, hyponatremia, hyperbilirubinema; febrile neutropenia), and 2 of 3 pts in cohort 3 (febrile neutropenia, hypokalemia; febrile neutropenia). 1 pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. Most common grade 3/4 adverse events were neutropenia (7), leukopenia (5). Febrile neutropenia occurred in 4 patients (21%). No objective responses were seen. Two patients (breast and lung) had prolonged stable disease for 25 and 20 cycles respectively. CONCLUSIONS: Based on this experience we recommend vinflunine 300 mg/m(2) and pemetrexed 500 mg/m(2) in combination every 3 weeks for future study. At these doses, the combination of vinflunine and pemetrexed was tolerable in this heavily pretreated population. Hematologic toxicity, including febrile neutropenia, was prominent.

A phase I evaluation of the combination of vinflunine and erlotinib in patients with refractory solid tumors.

PURPOSE: Epidermal growth factor receptor (EGFR) inhibition may overcome chemotherapy resistance by inhibiting important anti-apoptotic signals that are constitutively activated by an overstimulated EGFR pathway. METHODS: This phase I dose escalation trial assessed the safety and efficacy of vinflunine, a novel vinca alkaloid microtubule inhibitor, with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with refractory solid tumors. RESULTS: Seventeen patients were treated, 10 with continuous erlotinib, and 7 with intermittent erlotinib. At dose level 1, vinflunine 280 mg/m(2) IV day 1 and erlotinib 75 mg PO days 2-21 ("continuous erlotinib") in 21 day cycles, two of four patients experienced DLTs. At dose level -1 (vinflunine 250 mg/m(2) every 21 days and erlotinib 75 mg/day), two of six patients experienced DLTs. The study was amended to enroll to "intermittent erlotinib" dosing: vinflunine day 1 and erlotinib days 2-15 of a 21 day cycle. Two of seven experienced DLTs and the study was terminated. One patient with breast cancer had a partial response; three had stable disease ≥ 6 cycles. All were treated in the continuous erlotinib group. CONCLUSIONS: Given the marked toxicity in our patient population, the combination of vinflunine and erlotinib cannot be recommended for further study with these dosing schemas.

Balancing the CAR T: perspectives on efficacy and safety of CAR T-cell therapy in hematologic malignancies.

Chimeric antigen receptor (CAR) T-cell therapy is an example of how immunotherapy is revolutionizing the treatment of hematologic malignancies with unprecedented response rates in patients with relapsed/refractory lymphoma, multiple myeloma, and acute lymphoblastic leukemia. The process for administering CAR T-cell therapy is complex, with multiple steps including CAR T-cell manufacturing, lymphodepleting chemotherapy, cellular therapy infusion, and management of short-term and long-term toxicities. While effective, broad use of CAR T-cell therapies is limited by potential for life-threatening toxicities, challenges related to manufacturing a patient-specific product, high costs and inadequate reimbursement, and incomplete or unsustained disease response. Pharmacists are intricately involved in the process of providing CAR T-cell therapy both at the organizational level of budgeting and coordinating therapy and in direct patient care roles providing counseling and support for adverse effect management. Research in CAR T-cell therapy is expected to improve tolerability and expand indications to more types of malignancies and earlier phases of disease. Managed care professionals should have an understanding of the clinical trial data and place in therapy in lymphoma, myeloma, and acute lymphoblastic leukemia as well as guideline recommendations for adverse effect management associated with CAR T-cell therapies.

Bevacizumab: a treatment option for recurrent glioblastoma multiforme.

OBJECTIVE: To review the available literature evaluating the effect of bevacizumab on progression-free survival when used in combination with irinotecan for recurrent glioblastoma multiforme (GBM). DATA SOURCES: Searches of MEDLINE (1966-June 2008), the Cochrane Library, and International Pharmaceutical Abstracts (1970-June 2008) were conducted using the terms bevacizumab, irinotecan, and glioblastoma multiforme. STUDY SELECTION AND DATA EXTRACTION: The search was limited to studies conducted in humans. All articles identified from the data sources were evaluated. All clinical trials evaluating the efficacy and safety of bevacizumab in the treatment of recurrent GBM were included in the review. DATA SYNTHESIS: Hypoxia, mutagenesis, and the secretion of various growth factors can all lead to production of vascular endothelial growth factor (VEGF), a proangiogenic growth factor, and angiogenesis in GBM. Neoplastic progression is dependent on angiogenesis, and anti-VEGF therapy has been successful in multiple disease states. However, there are currently no available anti-VEGF therapies approved for treatment of GBM. Bevacizumab is a humanized monoclonal antibody that binds to and inhibits the activity of VEGF. When compared with data from clinical trials that use single chemotherapeutic agents in recurrent GBM, the addition of bevacizumab to cytotoxic chemotherapy, such as irinotecan, appears to improve progression-free survival in patients progressing on the standard of care, with a 6-month progression-free survival rate of 46%. Bevacizumab is well tolerated by most patients, with modest risk (11% in Phase 2 trials) of venous thromboembolism. CONCLUSIONS: Although the combination of bevacizumab and irinotecan is producing positive results in patients with recurrent GBM, larger, randomized clinical trials need to be performed to determine the magnitude of the benefit from bevacizumab. Bevacizumab administered biweekly at a dose of 10 mg/kg in combination with irinotecan may improve progression-free survival.

Nelarabine: a novel purine antimetabolite antineoplastic agent.

BACKGROUND: Nelarabine was approved by the US Food and Drug Administration (FDA) in October 2005 for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. OBJECTIVES: This article reviews the pharmacology, mechanism of action, and pharmacokinetic and pharmacodynamic properties of nelarabine. Also reviewed are nelarabine's clinical efficacy in T-ALL, T-LBL, and other hematologic malignancies; its toxicity profile, dosage, and administration; and areas of ongoing and future research. METHODS: Relevant literature was identified through searches of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and the American Society of Hematology database (2003-2006) using the terms nelarabine, Arranon, 506U78, and 2-amino-6-methoxypurine arabinoside. The reference lists of the identified articles were searched for additional sources. Product information obtained from the manufacturer of nelarabine was consulted, as were the FDA reviews of nelarabine. All identified publications were considered, and those meeting the objectives of this review were included. RESULTS: Nelarabine, a soluble prodrug of 9-beta-D- arabinofuranosylguanine (ara-G), is a novel purine antimetabolite antineoplastic that preferentially accumulates in T-cells. Ara-G is rapidly phosphorylated in T-cells to ara-G triphosphate (ara-GTP), which exerts cytotoxic effects. Renal elimination of ara-G is decreased in patients with mild to moderate renal impairment; however, no dose adjustment is recommended. Accumulation of ara-GTP occurs in T-cells in a dose-dependent manner, leading to preferential cytotoxicity. Nelarabine has activity in T-cell malignancies, as evaluated in 2 Phase I and 5 Phase II studies. It received accelerated approval from the FDA based on the resuits of 2 Phase II trials, one in pediatric patients (PGAA 2001) and the other in adults (CALGB 19801). In PGAA 2001, patients with T-ALL in first relapse (n = 33) had an objective response rate of 55% (16 with a complete response [CR] and 2 with a partial response [PR]), and those with T-ALL in second relapse (n = 30) had an objective response rate of 27% (7 CR and 1 PR). Among patients with central nervous system-positive T-ALL or T-cell non-Hodgkins lymphoma (T-NHL) (n = 21), 33% had an objective response (5 CR and 2 PR); among patients with T-ALL or T-NHL with extramedullary relapse (n = 22), 14% had a PR. CALGB 19801 included 39 adult patients with T-cell malignancies, of whom 7 (18%) had a CR and an additional 2 (5%) had a CR without full hematologic recovery. The recommended dose of nelarabine in adults is 1500 mg/m(2) IV given over 2 hours on days 1, 3, and 5, repeated every 21 days; the recommended dose in pediatric patients is 650 mg/m(2) IV given over 1 hour for 5 consecutive days, repeated every 21 days. Dose-limiting toxicities observed in the Phase I and II trials included central and peripheral neurotoxicity. Symptoms of central neurotoxicity included somnolence, seizures, dizziness, confusion, and ataxia; symptoms of peripheral neurotoxicity included paresthesias, pain in the extremities, and peripheral neuropathy. CONCLUSIONS: Nelarabine is indicated for the treatment of T-ALL and T-LBL that has not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. Objective response rates in Phase II clinical trials of nelarabine have ranged from 11% to 60%. Use of nelarabine is limited by potentially severe neurotoxicity.

Allopurinol as adjuvant therapy in poorly responsive or treatment refractory schizophrenia.

OBJECTIVE: To review the available literature evaluating the effectiveness of allopurinol for poorly responsive or treatment refractory schizophrenia. DATA SOURCES: Searches of MEDLINE (1966-October 2006), the Cochrane Library, and International Pharmaceutical Abstracts (1970-October 2006) were conducted using the terms allopurinol and schizophrenia. Limits were set to select studies conducted in humans. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated. All case reports or clinical trials located were included in the review. DATA SYNTHESIS: Dopamine has been implicated for many years in the pathophysiology of schizophrenia, and the typical antipsychotics, via blockade of dopaminergic neurotransmission, have provided relief for patients with positive symptoms. However, because dopamine blockade does not relieve all symptoms of schizophrenia, it is now evident that many neurotransmitters may be involved in the pathogenesis of schizophrenia. Therefore, atypical antipsychotics, which target multiple neurotransmitters, have emerged as first-line therapies. An evolving body of evidence also supports a purinergic hypothesis for schizophrenia. Increased adenosinergic transmission is thought to reduce the affinity of dopamine agonists for dopamine receptors. Allopurinol, a xanthine oxidase inhibitor, may increase circulating pools of adenosine and may ultimately have antipsychotic and anxiolytic effects. Growing evidence for use of allopurinol as adjunctive therapy has been reported in both case reports and small clinical trials. CONCLUSIONS: Clinical trials show that adjuvant allopurinol may provide benefit to patients who are poorly responsive to current treatments for schizophrenia. Allopurinol is well tolerated by most patients. However, larger, randomized clinical trials need to be performed to determine the magnitude of this benefit, whether allopurinol should be routinely used as adjuvant therapy to antipsychotics, and which patient population is most likely to benefit from allopurinol use. For patients with limited options, allopurinol in doses of 300 mg once or twice daily may improve psychotic symptoms, especially refractory positive symptoms.

A Study of Layered Learning in Oncology.

Objective. To explore use of pharmacy learners as a means to expand pharmacy services in a layered learning practice model (LLPM), to examine whether an LLPM environment precludes achievement of knowledge-based learning objectives, and to explore learner perception of the experience. Design. An acute care oncology pharmacy practice experience was redesigned to support the LLPM. Specifically, the redesign focused on micro discussion, standardized feedback (eg, rubrics), and cooperative learning to enhance educational gain through performing clinical activities. Assessment. Posttest scores evaluating knowledge-based learning objectives increased in mean percentage compared to pretest values. Learners viewed the newly designed practice experience positively with respect to perceived knowledge attainment, improved clinical time management skills, contributions to patient care, and development of clinical and self-management skills. A fifth theme among students, comfort with learning, was also noted. Conclusion. Layered learning in an oncology practice experience was well-received by pharmacy learners. Data suggest a practice experience in the LLPM environment does not preclude achieving knowledge-based learning objectives and supports further studies of the LLPM.

The use of Erwinia asparaginase for adult patients with acute lymphoblastic leukemia after pegaspargase intolerance.

Asparaginase administration has become a crucial component of front-line pediatric and pediatric-insipired multi-agent regimens for the treatment of acute lymphoblastic leukemia (ALL). The aim of this retrospective study was to assess the safety and feasibility of switching to Erwinia asparaginase after pegaspargase intolerance in adult ALL patients treated at Memorial Sloan Kettering Cancer Center. Our analysis included 10 patients, with a median age of 39 years (range 20-72), male predominance (90%), and a typical B-cell to T-cell ratio (70:30%) for ALL. Nine patients were switched to Erwinia asparaginase after pegaspargase hypersensitivity and one patient after grade 4 hyperbilirubinemia secondary to pegaspargase. With Erwinia asparaginase, no hypersensitivity reactions occurred and no patient developed other known clinical asparaginase-related toxicities. Laboratory adverse effects consisted of mostly mild elevation in liver enzymes. No morphologic relapses have occurred in any patient switched to Erwinia asparaginase in first remission at a follow up of 0.4-34.6 months. These findings are unique in that all of our patients received Erwinia asparaginase after hypersensitivity or intolerance to pegaspargase and 50% of them were older than 40 years of age, a population with very limited Erwinia asparaginase data. Our observations provide preliminary information that treatment with Erwinia asparaginase can proceed as scheduled in adult patients, despite pegaspargase hypersensitivity and possibly liver intolerance.

Expanding care through a layered learning practice model.

PURPOSE: The outcomes of a patient-centered layered learning practice model (LLPM) in which the clinical specialist acted as the attending pharmacist and managed a pharmacy team to provide direct patient care were evaluated. METHODS: Two 30-day evaluations were conducted on the acute care malignant hematology and medical oncology services of the University of North Carolina Medical Center in 2011. The primary objective of this study was to design an LLPM that used a team to expand the pharmacist care services offered. The primary outcome was the frequency of pharmacy team encounters at discharge (medication reconciliation and counseling), termed the discharge capture rate. RESULTS: During the study months, 42 and 78 malignant hematology and medical oncology patients were eligible for study inclusion, respectively. The overall discharge capture rate was 51%. Sixty-one patients received discharge medication reconciliation services during patient counseling. Patients included in the malignant hematology group received a mean of 11 prescriptions at discharge, compared with 9.83 in the medical oncology group. Means of 1.26 and 2.1 medication-related problems per patient were identified in the malignant hematology and medical oncology studies, respectively, during discharge medication reconciliation. The overall mean face time spent per patient was 21.3 minutes. CONCLUSION: Patients in malignant hematology and medical oncology services were counseled and provided discharge medication reconciliation by a pharmacy student or resident whose activities were managed and reviewed by an attending pharmacist using an LLPM, resulting in an improvement in all clinical outcomes and measures.