Jack T Seki

Therapeutic drug monitoring for triazoles: A needs assessment review and recommendations from a Canadian perspective

Therapeutic drug monitoring (TDM) is necessary for certain drugs to ensure that the levels are sufficient to be effective, but not so high as to cause adverse effects. This review summarizes the literature regarding TDM for newer-generation extended-spectrum triazoles, including when TDM may be necessary for each drug and why, and laboratory techniques used for the measurement of levels of these drugs. The document includes recommendations for the use of TDM for each triazole that is discussed.

CNS Relapses of Acute Promyelocytic Leukemia after All-Trans Retinoic Acid

OBJECTIVE: To review the role of all-trans retinoic acid (ATRA) and arsenic trioxide in central nervous system (CNS) relapses of acute promyelocytic leukemia (APL). CASE SUMMARY: A 69-year-old white man diagnosed with APL presented with bleeding diathesis. His molecular and cytogenetic studies were positive for promyelocytic leukemia—retinoic acid receptorα (PML-RARα) and t(15;17) transformation. Complete molecular and cytogenetic remission was achieved with ATRA, daunorubicin, and cytarabine. Within 6 months, the patient was readmitted for investigation of severe global headaches and an ataxic gait. His peripheral blood and cerebral spinal fluid were positive for PML-RARα fusion protein. Intrathecal chemotherapy and radiation, as well as ATRA, were the main treatment modalities provided. Molecular and cytogenetic remission was again obtained. Three months later, a second relapse occurred in the CNS and the peripheral blood. DISCUSSION: APL is typically treated with anthacycline-based chemotherapy and ATRA. Approximately 85–95% of patients achieve complete remission (CR); however, the relapse rate has been reported to be about 30–40%. A thorough literature search (MEDLINE, EMBASE, CANCERLIT, 1966–January 2002) revealed only 54 cases of extramedullary disease, of which 35 involved the CNS. CONCLUSIONS: The introduction of ATRA has improved patient survival dramatically. APL relapse, in general, has been in part attributable to repetitive or prolonged exposure to ATRA and the possibility of additional chromosomal changes, making the disease more refractory to treat. Given the evidence, one could argue that, with repeated ATRA treatment, CR duration may be shortened. However, limited data are available to guide the appropriate management of APL relapsed to the CNS with either ATRA, chemotherapy, or arsenic trioxide. In our opinion, treatment using arsenic trioxide is an unconventional option worthy of exploring.

Chemotherapy-induced infiltrative pneumonitis cases in breast cancer patients

A number of chemotherapy drugs are well known to cause various histopathologic patterns of lung injury. The incidence of chemotherapy-induced infiltrative pneumonitis is rare and the diagnosis is difficult due to the nonspecific clinical and radiological presentations. However, it can cause significant morbidity and mortality in cancer patients. There is no consensus on the treatment of this adverse event, but prompt diagnosis and intervention is important as fatal outcomes have been reported. We present five cases of chemotherapy-induced infiltrative pneumonitis in breast cancer patients involving docetaxel, paclitaxel, gemcitabine and cyclophosphamide.

Acute Tumor Lysis Syndrome Secondary to Hydroxyurea in Acute Myeloid Leukemia

OBJECTIVE: To report 2 cases of acute tumor lysis syndrome (ATLS) associated with hydroxyurea treatment. CASE SUMMARY: A 79-year-old woman diagnosed with chronic lymphocytic leukemia presented with an acute blastic transformation. She was promptly hydrated, started on allopurinol, and treated with hydroxyurea. About 24 hours later, her biochemistry panel showed parameters consistent with ATLS when compared with pretreatment levels. The second case was a 76-year-old man newly diagnosed with acute myeloid leukemia presenting with high blast fraction. He was given appropriate hydration and allopurinol prophylaxis, and was started on high-dose hydroxyurea treatment. He became symptomatic after 12 hours and results of his blood work were consistent with ATLS. DISCUSSION: ATLS is a well-known metabolic disturbance that occurs after cell destruction of rapidly growing tumors. In standard doses, hydroxyurea leads to cell death in the S phase and is not thought to cause significant cell lysis. However, in large doses, it possibly acts by a different mechanism and had a direct cytolytic effect associated with ATLS in our patients. CONCLUSIONS: Although ATLS caused by hydroxyurea appears to be rare, patients at risk should be closely monitored for this complication. An objective causality assessment using the Naranjo probability scale revealed that the adverse drug reaction was probable between ATLS and hydroxyurea therapy in these 2 patients.

Managing skin toxicities related to panitumumab

BACKGROUND Dermatologic toxicities from targeted agents such as panitumumab can interfere with cancer treatment. OBJECTIVE We sought to evaluate the rash assessment and management in a consecutive patient cohort who received panitumumab for colorectal cancer treatment. METHODS This was a retrospective chart review. RESULTS Skin toxicity, consisting of papulopustular rash, was experienced by 32 of 34 patients. The majority (85%) developed the rash by the end of the second infusion cycle. Patients presented with a mild (41%), moderate (38%), and severe (21%) rash, and progressed to an extensive rash without appropriate treatment. A grading system was used for 65% of patients to document severity. LIMITATIONS Small sample size limited power in analysis. Rash severity had to be inferred based on rash description and management in 11 of the patients. CONCLUSION Dermatologic toxicities related to panitumumab are common; however, the way they are reported and managed varies among physicians. To prevent progression, toxicities must be assessed and treated early and aggressively, according to severity grading. Dermatologists could aid oncologists in choosing the best management strategies.

Serum Voriconazole Level Variability in Patients with Hematological Malignancies Receiving Voriconazole Therapy

Voriconazole is an important antifungal agent used to treat invasive fungal infections; however, its administration can be difficult because of the narrow range between the level required for therapeutic efficacy and the level at which there is risk for hepatic and neurological toxicity. The purpose of this study was to elucidate the relationships among oral dosage, voriconazole levels and liver enzyme levels among leukemia patients.

Venous thromboembolism prevention during asparaginase-based therapy for acute lymphoblastic leukemia.

BACKGROUND Venous thromboembolism (vte) is a recognized complication in patients treated with asparaginase-containing chemotherapy regimens; the optimal preventive strategy is unclear. We assessed the safety and efficacy of prophylaxis using low-dose low molecular weight heparin in adult patients with acute lymphoblastic leukemia in complete remission treated with an asparaginase-based post-remission chemotherapy regimen. METHODS As part of the intensification phase of the Dana-Farber Cancer Institute 91-01 regimen, asparaginase was administered weekly to 41 consecutive patients for 21-30 weeks; these patients also received prophylaxis with enoxaparin 40 mg daily (60 mg for patients ≥80 kg). Outcomes were assessed against outcomes in a comparable cohort of 99 patients who received the same chemotherapy regimen without anticoagulation prophylaxis. RESULTS The overall rate of symptomatic venous thrombosis was not significantly different in the prophylaxis and non-prophylaxis cohorts (18.92% and 21.74% respectively). Among patients receiving prophylaxis, vte occurred in higher proportion in those who weighed at least 80 kg (42.86% vs. 4.35%, p = 0.0070). No major bleeding complications occurred in the prophylaxis group (minor bleeding: 8.1%). CONCLUSIONS Prophylaxis with low-dose enoxaparin during the intensification phase was safe, but was not associated with a lower overall proportion of vte.

Retinoic acid syndrome after one dose of all-transretinoic acid

All-trans-retinoic acid (ATRA) is typically used as a first line agent in the treatment of acute promyelocytic leukaemia (APL), achieving complete remission (CR) rates (incombination with chemotherapy) of about 90%. One of the drawbacks of the use of ATRA is that up to 30% of patients can present with retinoic acid syndrome (RAS), which can be fatal in some patients. We describe a case of RAS after only one dose of ATRA, which to our knowledge has not previously been identified in the literature. The pathophysiology and treatment of APL is presented. A clinical description of RAS is outlined, and an evaluation of risk factors for developing RAS is reviewed.

Examining the safety and efficacy of a chemotherapy dosing method in Allogeneic Stem Cell Transplant patients of extreme body size

Background. There is no consensus on a universal dosing method for calculating high-dose chemotherapy in allogeneic Stem Cell Transplant (SCT) patients. The Metropolitan Life (Met-Life) Insurance Company’s weight—height tables have been used to determine body weight for chemotherapy dosing for SCT, however no formal study has been done to determine if the Met-Life weight— height tables can be used for chemotherapy dosing in SCT. We retrospectively studied the use of Met-Life weight—height tables for chemotherapy dosing in SCT. Our goal is to determine if patients with extremes of body size who had undergone an SCT and were dosed according to the Met-Life weight— height tables had an increase of Treatment Related Morbidity (TRM) or mortality or relapse. Patients and Methods. Patients were grouped into three different treatment regimens, cyclophosphamide/TBI, busulphan/cyclophosphamide, and AraC/cyclophosphamide/TBI. Patients in each treatment regimen were further divided into five equal groups based on weight. Treatment related morbidity and mortality was evaluated by comparing the lowest and highest quintiles to the middle quintiles within each treatment regimen. Result. Data from 262 patients was evaluated in this study. Overall, there was not an increase in TRM or mortality or in relapse in patients with extremes of body size. Conclusion. The Met-Life weight—height tables could be used to dose patients undergoing allogeneic SCTs. Additional prospective studies would need to be done comparing other chemotherapy dosing methods with the Met-Life weight—height tables to further validate this conclusion.

Human albumin eye drops as a therapeutic option for the management of keratoconjunctivitis sicca secondary to chronic graft-versus-host disease after stem-cell allografting

BACKGROUND Keratoconjunctivitis sicca from chronic graft-versus-host disease (cgvhd) after allogeneic stem cell transplantation is common, leading to severe corneal damage and blindness if not treated. We retrospectively examined the efficacy and safety of pooled human albumin eye drops (haeds) for symptom relief in 40 stem-cell transplantation patients after other alternatives had failed. METHODS The Common Terminology Criteria for Adverse Events (version 4.0) and the cgvhd grading scale were used to compare response in the patients during January 2000 and July 2013. In addition, on days 1 and 30, the haeds were subjected to quality assurance testing for sterility, oncotic pressure, albumin measurement, viscosity, pH, and purity by protein electrophoresis. RESULTS Use of haeds resulted in symptom relief for 37 patients (92.5%); 3 patients (7.5%) failed to improve with use of haeds (p ≤ 0.0001). Of the 37 patients having symptom relief, 7 (19%) improved from grade 3 to no dry eye symptoms. Proportionately, post-treatment symptom improvement by two grade levels, from 3 to 1 (70%), was significantly higher than improvement by one grade level, from 3 to 2 (11%) or from 2 to 1 (19%, p ≤ 0.0001). Time to symptom relief ranged from 2 weeks to 28 weeks. Of the 40 patients, 38 (95%) had no adverse reactions. Days 1 and 30 quality assurance testing results were equivalent. CONCLUSIONS Complications of keratoconjunctivitis sicca were well managed and well tolerated with haeds when other remedies failed. Quality assurance testing confirmed that haeds were safe and stable in extreme conditions.