Review article: second-generation thrombopoietin agents for treatment of chronic idiopathic thrombocytopenic purpura in adults.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of two new thrombopoietic (TPO) receptor agonists, romiplostim and eltrombopag, in the treatment of chronic idiopathic thrombocytopenic purpura (ITP) in adults. DATA SOURCES: A MEDLINE search was conducted (1966 to March 2009) using the search terms romiplostim, AMG 531, eltrombopag, SB-497115, idiopathic thrombocytopenic purpura. Articles on phases 1-3 clinical trials in patients with ITP were identified and reviewed. References from manufacturer information, and abstracts from recent hematology meetings, were also evaluated. STUDY SELECTION AND DATA EXTRACTION: Controlled clinical trials evaluating romiplostim and eltrombopag for treatment of chronic ITP in adults were selected from the data sources. All published relevant abstracts were also included. DATA SYNTHESIS: Limited randomized controlled trials and open-label ongoing long-term extension studies for romiplostim and eltrombopag, have shown that both TPO agonists are effective in improving the platelet count and reducing the bleeding episodes in adult patients with ITP unresponsive to at least one standard treatment. The most common adverse events associated with the drugs are mild to moderate headaches. The use of these agents has also been associated with rare but serious side-effects including bone marrow reticulin fibrosis, thrombotic events, and myeloid malignancies. CONCLUSIONS: Until more long-term follow-up data regarding the safety, as well as comparative studies that further define the role of TPO agonists versus other agents in the treatment of chronic ITP are available, these agents should be reserved for patients with ITP refractory or intolerant to standard therapy.

Role of chemotherapy and rituximab for treatment of posttransplant lymphoproliferative disorder in solid organ transplantation.

OBJECTIVE: To evaluate the role of chemotherapy and/or rituximab for treatment of posttransplant lymphoproliferative disorder (PTLD) in solid organ transplantation. DATA SOURCES: A MEDLINE search (1966-May 2007) was conducted using the key words posttransplant lymphoproliferative disorder, solid organ transplantation, chemotherapy, and rituximab. References of relevant articles and abstracts from recent hematology, oncology, and transplantation scientific meetings (2004-May 2007) were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Prospective and retrospective studies identified from the data sources were evaluated, and all information deemed relevant was included for this review. DATA SYNTHESIS: Overall response rates ranged from 53% to 68%, 25% to 83%, and 74% to 100% for rituximab monotherapy, chemotherapy, and chemotherapy plus rituximab, respectively. Positive response to treatment was influenced by prognostic factors, including presence of Epstein-Barr virus in tumor cells, normal lactate dehydrogenase levels, good performance status, early disease onset after transplantation, and early disease stages. These factors in study patients likely contribute to the variability in response rates seen between treatment options. Severe adverse effects, ranging from grade 3 neutropenia to infection resulting in death, occurred more frequently in patients receiving chemotherapy than in patients receiving only rituximab. CONCLUSIONS: Although reduction in immunosuppressive medications remains the first-line therapy for PTLD treatment, many cases do not respond to this treatment alone, especially monomorphic or more aggressive cases of lymphoma. Therefore, it is reasonable to begin active treatment including rituximab and/or chemotherapy initially, along with reduction in immunosuppression in many cases. Further prospective, comparative studies are urgently needed to confirm the efficacy of these treatment strategies as well as to clarify which subset of patients may benefit most from them.

Treatment of Burkitt's lymphoma during pregnancy.

OBJECTIVE: To report a case of both successful maternal treatment outcome and normal fetal outcome in a patient who was diagnosed with Burkitt's lymphoma (BL) and aggressively treated with 6 different chemotherapy agents during the second and third trimesters of pregnancy. CASE SUMMARY: A 21-year-old white woman was diagnosed with stage II BL of the head and neck at 26 weeks' gestation. She was treated with 2 cycles of systemic intensive polychemotherapy, including cyclophosphamide, vincristine, doxorubicin, cytarabine, etoposide, ifosfamide, mesna, and intrathecal cytarabine with growth factor support during the second and third trimesters. She delivered a healthy, premature boy 6 weeks after diagnosis. At a follow-up 1 year after diagnosis, the patient remained disease-free and the baby remained healthy. DISCUSSION: The prognosis of BL depends on the stage at diagnosis, as well as treatment aggressiveness. Previous reports indicate that most patients diagnosed with BL during pregnancy received either no treatment or only one chemotherapy agent, and the majority ultimately died of rapidly progressive diseases. The fetal outcomes seem to depend primarily on the time of exposure to chemotherapy and/or radiation, doses, specific chemotherapy agent given, and frequency of treatment during pregnancy. Limited retrospective data suggest that chemotherapy given after the first trimester is relatively safe and does not adversely affect the short- and long-term fetal outcomes. CONCLUSIONS: Treatment of BL during pregnancy can be very challenging because an aggressive approach is the main key to maximize the patient's long-term disease-free survival. However, the health of the unborn child should also be a concern when choosing treatment. This case demonstrates that combination chemotherapy given after the first trimester did not result in any congenital malformations or acute adverse effects in the fetus. Long-term follow-up of the child remains necessary to evaluate possible long-term complications.

Pertuzumab for the treatment of human epidermal growth factor receptor type 2-positive metastatic breast cancer.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of pertuzumab in patients with metastatic human epidermal growth factor receptor type 2 (HER2)-positive breast cancer are reviewed. SUMMARY: Disease progression in HER2-positive breast cancer is often due to resistance to or a lack of efficacy of trastuzumab-based anti-HER2 therapy. Pertuzumab is the first humanized monoclonal antibody in a new class of drugs, the HER dimerization inhibitors, approved by the Food and Drug Administration for the first-line treatment of patients with metastatic HER2-positive breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Since pertuzumab binds to a different epitope than trastuzumab, combination therapy with pertuzumab and trastuzumab results in a more complete blockade of HER2 signaling than trastuzumab monotherapy. The efficacy of adding pertuzumab to trastuzumab-docetaxel dual therapy was demonstrated in a pivotal randomized multicenter Phase III trial, which showed a significant benefit in terms of progression-free survival, with improved overall survival, in favor of the triple therapy as an initial regimen in treatment-naive patients with metastatic HER2-positive breast cancer. The combination of pertuzumab and trastuzumab has been found to have a tolerable toxicity profile. As clinical trials of pertuzumab for adjuvant, neoadjuvant, and metastatic-disease treatment continue, its role in the treatment of HER2-positive breast cancer will continue to evolve. CONCLUSION: Pertuzumab, a novel HER2 dimerization inhibitor, has been shown to be effective in the treatment of metastatic HER2-positive breast cancer when used in combination with trastuzumab and docetaxel and is recommended for first-line therapy.

Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs.

Oncology pharmacists face a constant challenge with patients who cannot swallow oral anticancer drugs, making extemporaneous oral liquid preparation a requirement. Improper extemporaneous preparation of these agents, especially with the traditional chemotherapy with a narrow therapeutic index, may increase the risk of over- or underdosing. In community pharmacies, multiple barriers exist that prevent these pharmacies from preparing extemporaneous oral anticancer drug formulations for a patient's use at home. In a home setting, patients or caregivers without proper counseling and education on how to safely handle chemotherapy are at increased risk for exposure to these drugs. Based on a review of the literature, compounding recipes are available for 46% of oral anticancer agents. A paucity of data exists on dose uniformity, bioequivalence, and stability of extemporaneous oral liquid formulations of anticancer drugs. Pharmacists must have an understanding of the basic scientific principles that are an essential foundation for the proper preparation of extemporaneous oral anticancer liquid formulations. The collaborative effort of a multidisciplinary team can also help identify different barriers in the community setting, especially in areas where community pharmacies may lack resources for the extemporaneous compounding of oral chemotherapy, and to find ways to coordinate better pharmaceutical care. There are great opportunities for oncology pharmacists, as well as community pharmacists, as a resource for educating and monitoring patients receiving oral chemotherapy to ensure dosing accuracy, safe administration, and proper disposal of hazardous drugs. Development of national guidelines to promote standards of practice in the community and/or home setting is urgently needed to help improve the safety of dispensing and handling oral chemotherapeutic agents, including extemporaneously compounded oral liquid formulations of these drugs.

Capecitabine-associated cerebellar ataxia.

PURPOSE: A case of capecitabine-associated cerebellar ataxia is presented. SUMMARY: A 65-year-old white woman with stage IV colorectal cancer with liver metastasis was started on a chemotherapy regimen of capecitabine, oxaliplatin, and bevacizumab, given every three weeks. She tolerated the first two treatment cycles fairly well without major toxicities. The capecitabine dosage was started at 2000 mg daily for 14 days during the first cycle and increased to 2500 and 3000 mg daily during the second and the third cycles, respectively. On day 5 of the third cycle, the patient reported increased nausea, fatigue, and sleepiness, and the dosage of capecitabine was subsequently reduced to 2500 mg daily. On day 12 of the fourth treatment cycle, she reported ongoing lightheadedness and progressive gait disturbance with worsening ataxia over the past 3 days. Her capecitabine dosage was further reduced to 2000 mg daily, and the time between treatment intervals was increased to four weeks. The patient continued to experience intermittent, but less severe, ataxia during the fifth treatment cycle. On the day before the seventh cycle was to begin, she had ataxic gait and could not walk without assistance. Subsequent magnetic resonance imaging of the brain revealed no evidence of brain metastasis or cerebellar abnormality. The chemotherapy was postponed for a total of six weeks until the ataxia completely resolved. Her chemotherapy was ultimately discontinued due to disease progression. Her neurologic symptoms did not recur. CONCLUSION: A patient receiving capecitabine-containing chemotherapy developed persistent but reversible cerebellar ataxia.

The need for routine bleomycin test dosing in the 21st century.

OBJECTIVE: To review the clinical evidence for routine use of bleomycin test dosing. DATA SOURCES: English-language review articles, references from retrieved articles, case reports, and clinical trials were identified from a MEDLINE literature search (1966-July 2005). Key search terms included bleomycin, test dose, anaphylactic reactions, and hypersensitivity. Information from an unpublished E-mail survey, the manufacturer, and the Internet was also used. DATA SYNTHESIS: Early clinical trials and isolated case reports suggest that bleomycin-induced acute hypersensitivity reactions occur in 1% of patients with lymphoma and <0.5% of those with solid tumors. The reactions are mainly characterized by high-grade fever, chills, hypotension, and in a few cases, cardiovascular collapse, which can lead to death. The exact mechanism of these reactions is unclear, but is thought to be related to the release of endogenous pyrogens from the host cells. Evidence does not suggest any correlation between doses and the onset or severity of the reactions. Supportive care, including hydration, steroids, antipyretics, and antihistamines, may resolve the symptoms. However, it may not completely prevent recurrences. CONCLUSIONS: The incidence of acute hypersensitivity or hyperpyrexic reactions associated with bleomycin is very low, but the reaction is potentially fatal. Clinicians should monitor their patients for any signs and symptoms of acute hyperpyrexic reactions during bleomycin administration. Since the onset of the reactions can occur with any dose of bleomycin and at any time, routine test dosing does not seem to predict when drug reactions may occur.

Recombinant factor VIIa in the treatment of non-hemophiliac bleeding.

OBJECTIVE: To review the clinical evidence for the use of recombinant factor VIIa (rFVIIa) in the prevention and/or treatment of bleeding in non-hemophiliac patients. DATA SOURCES: A MEDLINE search (1966-December 2004) was conducted to identify pertinent literature. Results were limited to English-language reports and clinical trials. References of relevant articles and selected abstracts presented at scientific meetings were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Human data from prospective and retrospective studies that examined the hemostatic effect of rFVIIa in non-hemophiliac patients were reviewed, with a focus on surgical prophylaxis, liver disease, intractable bleeding associated with trauma and surgery, and anticoagulation reversal. DATA SYNTHESIS: Results from limited controlled trials on the use of rFVIIa as an adjunct for prevention of bleeding in surgery and liver diseases have not been consistent. For treatment of intractable bleeding, earlier use of rFVIIa in one trauma trial was shown to decrease the number of blood transfusions, but no differences in terms of clinical outcomes were observed in all trials. Controlled trials do not suggest an increased risk of thrombotic events. Optimal dosing and timing of administration have yet to be defined. CONCLUSIONS: Until further prospective controlled data are available, it is recommended that conventional intervention for prevention and control of hemorrhage in non-hemophiliac patients should remain the standard of care. Close monitoring of coagulation parameters is recommended before, during, and after therapy, especially in high-risk patients. Pharmacoeconomic analysis may be useful to help control costs and maximize clinical benefits.