John Coutsouvelis

Effectiveness of a single fixed dose of rasburicase 3 mg in the management of tumour lysis syndrome

Tumour lysis syndrome (TLS) is a life-threatening oncological emergency characterized by hyperuricaemia, hyperkalaemia, hyperphosphataemia, and hypocalcaemia [1, 2] due to the rapid lysis of malignant cells, following the initiation of anticancer therapies [3]. Traditionally, therapy for TLS involved intensive hydration, urinary alkalinization and administration of allopurinol [4–6]. Newer guidelines now include rasburicase, with monitoring of electrolytes, white blood cell counts (WCC) and lactate dehydrogenase (LDH) concentrations [1, 7, 8]. Rasburicase, a recombinant urate oxidase enzyme, effectively decreases existing serum uric acid (UA) by oxidizing it to allantoin which is readily soluble and excretable [3]. Although the recommended dose is 0.2 mg kg−1 day−1 for 5–7 days [9], studies have shown the efficacious use of reduced doses for shorter periods of time and subsequent cost savings [5, 6, 10–17]. Expert guidelines by Coieffer et al. [7] in 2008 and Cairo et al. in 2010 [1] on the management of TLS recommend a rasburicase dose of 0.1–0.2 mg kg−1 on the first day, then repeated for up to 7 days [1] or as necessary [7]. We present an analysis of a fixed 3 mg dose of rasburicase administered to adult patients, treated at a tertiary referral centre. The study was approved by the Alfred Health Human Research Ethics Committee and the Monash University Human Research Ethics Committee. Demographic data were collected. Biochemical parameters (serum creatinine, serum UA, phosphate and LDH concentrations), at baseline, 24 h and 72 h after initial administration of rasburicase were recorded and compared. The institution guideline indicates rasburicase to be given before the first dose of chemotherapy in patients considered high risk for TLS. This includes a diagnosis of Burkitts lymphoma, acute lymhoblastic leukaemia, bulky non-Hodgkins lymphoma, lymphoblastic lymphoma or acute myeloid leukaemia with one or more of the following: serum UA>0.46 mmol l−1, white cell count (WCC) >50 × 109 l−1 or LDH >two times normal. Patients who were at an ongoing risk of TLS (i.e. elevated UA or LDH or multiple days of aggressive cytoreductive chemotherapy) were allowed a repeat dose of rasburicase 3 mg. Adherence to the guideline was measured. Forty-one patients received 42 courses of rasburicase over a 40 month period (Figure 1A). Diagnosis, demographic and baseline biochemical data are presented in Table 1. Figure 1 Summaryof rasburicase courses and uric acid concentrations. A) Summary of rasburicase courses administered. B) Median uric acid concentrations over time stratified by presentation a baseline. ♦, normal; ▪, hyperuricaemic; ▴, all ... Table 1 Patientcharacteristics Rasburicase was administered as per institution guidelines in 40 (95%) of the patients. Median serum UA concentrations were within normal range at 72 h in all groups; in those who presented with hyperuricaemia, in those who presented with normal baseline serum UA concentrations and overall (Figure 1B). The majority of patients received one dose of rasburicase 3 mg (Figure 1A). In 34 patient episodes requiring one dose only, there was a decline in the median (range) UA concentration from 0.44 mmol l−1 (0.13–1.15) at baseline to 0.22 mmol l−1 (0.02–0.66) at 24 h. This decrease was maintained at 72 h (P < 0.0001) with a median of 0.21 mmol l−1 (0.02–0.52). Serum creatinine concentrations were within normal range (60–105 μmol l−1) at baseline in 74% of patients, with 82% having a normal creatinine at 72 h. Hyperphosphataemia was present in 29% of patients at baseline and increased to 44% at 72 h. Eight patient episodes required more than one dose due to the ongoing risk of TLS. In these patients the median (range) baseline UA was 0.50 mmol l−1 (0.02–2.0), 0.33 mmol l−1 (0.02−1.10) at 24 h and 0.24 mmol l−1 (0.02−1.10) at 72 h (P < 0.0001). Of these patients only 52% had a normal creatinine at baseline, increasing to 83% at 72 h. Mean phosphate concentrations decreased over time but all patients remained hyperphosphataemic at 72 h. No hypersensitivity reactions were noted, no patients required haemodialysis and no deaths were related to the administration of rasburicase. Our results demonstrate that a single fixed dose of rasburicase 3 mg, repeated if required, should be the standard regimen in the management of TLS. Recent studies and published guidelines have shown cumulative support for the safe and efficacious use of off-label dosing regimens of rasburicase [1, 5–8, 10, 11, 16, 17]. A quarter of our patients presented with a baseline WCC>100 × 109 l−1 (Table 1), which is considered a high risk for developing TLS [1, 7]. The Product Information recommends rasburicase 0.1–0.2 mg kg−1 day−1 for 1–7 days [9]. We successfully used a fixed 3 mg dose for these patients. Our data support that presented by Trifilio et al. [11] in a recent study of 287 episodes, the largest published series at this time, of raised UA concentrations successfully treated with a single 3 mg dose of rasburicase, repeated if required. In our cohort, which was smaller in size, a single 3 mg dose was equally effective in both patients who had a normal baseline UA and those with hyperuracaemia. This differed from that published by Trifilio et al., where the single dose was more successful in patients with a lower baseline UA concentration. Our patient cohort also had a higher median LDH. Suboptimal management of hyperphosphatemia was identified in our cohort. More stringent monitoring of patient phosphate concentrations may be warranted in the future to minimize the risk of renal impairment. Serum creatinine, showing a gradual decrease with time, was used as a surrogate maker to indicate an improvement in renal function. Rasburicase was used in conjunction with allopurinol, urinary alkalinazation and intravenous hydration. This strategy is also supported by recent studies and recommendations [1, 11, 16], although the benefit of administering alkalinization with rasburicase needs further investigation [1, 7]. A single fixed 3 mg dose of rasburicase, in the setting of an institution guideline, was efficacious in the management of TLS.

Implementation of a pharmacist-initiated pharmaceutical handover for oncology and haematology patients being transferred to critical care units

Goals of workAn information gap with respect to specific therapies was identified when patients were transferred from the oncology and haematology unit (OHU) to the critical care units. The goal was to implement and evaluate the effectiveness of a pharmacist-initiated pharmaceutical handover (PIPH) for patients being transferred from the OHU to the critical care units at a major teaching hospital.Patients and methodsA PIPH process for the specific therapies of mouthcare, chemotherapy regimen, growth factors and antibiotics was developed. The PIPH was delivered in written format or combined written and verbal format. The impact of the PIPH was by assessment of recorded clinical pharmacist interventions. Data were analysed to evaluate any difference in the number of interventions relating to and the time to administration of the specific therapies.Main resultsData were available for 30 patient transfers in the pre-implementation group, with 22 transfers available in the post-implementation period. The number of interventions relating to the specific therapies was significantly reduced in the post-implementation group (144 vs 26; p < 0.0001). A significantly greater proportion of the specific therapies were administered on time in the post-implementation group (57% vs 96%; p < 0.0001).ConclusionsClinical pharmacists in the specialty area of oncology and haematology can improve the continuum of care when their patients are transferred to other units. By providing an accurate handover about specific therapies, there is an overall improvement in the prescribing and timely administration of these therapies.

Isavuconazole as salvage therapy for mucormycosis

Mucormycosis carries a high mortality rate with few therapeutic options available. We describe a man with pulmonary/splenic mucormycosis complicating hypoplastic myelodysplastic syndrome on a background of chronic kidney disease, who achieved a complete response with salvage isavuconazole therapy following intolerance of consecutive courses of liposomal amphotericin and posaconazole therapy.

Fludarabine, cytarabine, granulocyte-colony stimulating factor and amsacrine: an effective salvage therapy option for acute myeloid leukemia at first relapse

Abstract Improved therapeutic options for relapsing patients with acute myeloid leukemia (AML) are urgently needed. Poor outcomes following salvage therapy have been reported in those with short initial remission duration, adverse risk karyotype, prior allograft, older age, FLT3-internal tandem duplication (ITD) AML and prior high-dose cytarabine (HiDAC) induction therapy. We present a cohort of 58 patients (aged 18–70) treated with fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF) and amsacrine (FLAG-amsacrine) as salvage chemotherapy for AML at first relapse. 83% had received prior HiDAC-based therapy. The overall complete remission (CR/CR with incomplete blood count recovery [CRi]) rate was 59%, with median event-free survival (EFS) and overall survival (OS) of 6.9 and 10.6 months, respectively. FLAG-amsacrine was an effective bridge to allogeneic transplant with 38% successfully transplanted with excellent outcomes (median OS not reached). FLAG-amsacrine was also effective in elderly patients (≥60 years), with 61% achieving second remission. The regimen was well tolerated, with 30- and 42-day treatment-related mortality of 3.4% and 13.8%, respectively. Outcomes remained poor in those with short initial remission duration (<6 months). We conclude that FLAG-amsacrine is a useful salvage option for AML at first relapse.

Comparison of biosimilar filgrastim with originator filgrastim for peripheral blood stem cell mobilization and engraftment in patients with multiple myeloma undergoing autologous stem cell transplantation

Nivestim is a biosimilar approved for the same indications as Neupogen including the mobilization of autologous peripheral blood stem cells (PBSCs). The clinical efficacy and safety of Nivestim for this use have not been formally assessed in clinical trials.

High-dose cytarabine (24 g/m2) in combination with idarubicin (HiDAC-3) results in high first-cycle response with limited gastrointestinal toxicity in adult acute myeloid leukaemia.

Although induction chemotherapy comprising high‐dose cytarabine (HiDAC) in combination with idarubicin and etoposide or ‘ICE’ for adult acute myeloid leukaemia (AML) produces a complete remission rate of nearly 80%, gastrointestinal toxicity is significant. Omission of etoposide may produce similar clinical outcomes with potentially less gastrointestinal toxicity.

Timely initiation of chemotherapy: a systematic literature review in six priority cancers - results and recommendations for clinical practice.

This review evaluated the association between time‐to‐chemotherapy (TTC) and survival in six priority cancers. A systematic review of the literature was undertaken for papers indexed in the MEDLINE and Cochrane Library databases from the earliest index until April 2014. The methodology used has been published in a separate paper (Guidelines for timely initiation of chemotherapy: a proposed framework for access to medical oncology and haematology cancer clinics and chemotherapy services). The optimal timing of chemotherapy in breast cancer is unclear as available studies are of low quality, report inconsistent results and are limited to the adjuvant setting. However, increased TTC may have a negative prognostic impact, and delays beyond 4 weeks should be avoided. Studies suggest that the optimal timing for initiation of adjuvant chemotherapy for surgically resected colorectal cancer is 4–8 weeks post‐surgery. Timing of chemotherapy for metastatic colorectal cancer does not influence survival. There is a paucity of studies to guide the timing of chemotherapy for the treatment of lymphoma and myeloma; no definitive conclusions can be drawn, and clinician discretion should be applied. The optimal timing of chemotherapy in lung cancer is unclear; however, rapid tumour growth and poor disease prognosis suggest that delays should be avoided wherever possible. The optimal timing of chemotherapy in ovarian cancer is unclear as available studies are of low level, report inconsistent results and are limited to the post‐surgery setting; however, increased TTC may have a negative prognostic impact; therefore, delays beyond 4 weeks should be avoided.

The management of prolonged, isolated hyperbilirubinemia following cytarabine-based chemotherapy for Acute Myeloid Leukaemia

Background. Patients diagnosed with Acute Myeloid Leukaemia (AML) often receive cytarabine-based chemotherapy as standard treatment. Cytarabine is usually given in combination with other agents such as idarubicin. Such treatments are known to cause hepatic dysfunction characterized by a combination of jaundice, hyperbilirubinemia and increases in liver enzymes. Isolated hyperbilirubinemia is rarely reported. It is often difficult to identify a causative agent for the hepatic dysfunction, as there are often complicating factors such as sepsis. Aim: To report a case of isolated hyperbilirubinemia in a patient treated with cytarabine-based chemotherapy for AML. Clinical Details. After a diagnosis of AML the patient was admitted to hospital to receive induction chemotherapy consisting of high-dose cytarabine, idarubicin, and etoposide. All baseline laboratory results were normal, except the full blood evaluation that was consistent with AML. The chemotherapy was delivered over 7 days, and on the eighth day the patient had a bilirubin (BL) level of 27 umol/L (normal range 522 umol/L). All other liver function tests (LFT) were normal. This isolated hyperbilirubinemia remained for the rest of the patients admission, peaking on day 26, with a level of 255 umol/L. After a stay in the intensive care unit, the patient was discharged on day 45 with a bilirubin level of 33 umol/L. All other LFT remained unremarkable. Outcome. The isolated hyperbilirubinemia resolved slowly and on day 68, when the patient was re-admitted for further dose-reduced cytarabine, the BL level was 21 umol/L. The patient was successfully retreated with this lower dose regimen. Conclusion. Isolated hyperbilirubinemia is an uncommon presentation of cytarabine induced liver dysfunction. Resolution does occur but over a prolonged period. A lower dose of cytarabine for future treatment should be considered. J Oncol Pharm Practice (2009) 15: 107—110.

Defibrotide for the management of sinusoidal obstruction syndrome in patients who undergo haemopoietic stem cell transplantation

Sinusoidal obstruction syndrome, previously known as veno-occlusive disease (VOD/SOS), is a complication in patients undergoing haemopoietic stem cell transplantation (HSCT). Severe VOD/SOS, including progression to multi-organ failure, has resulted in a mortality of greater than 80%. Defibrotides varying pharmacological actions, particularly on endothelial cells, make it is a useful agent to consider for prophylaxis and treatment of VOD/SOS. Barriers to its routine use include the high acquisition cost and the fact that neither the oral or parenteral formulations are licensed products in many countries at this time. This review summarises available literature on the use of defibrotide in the management of VOD/SOS. Publications consist predominantly of single centre cohort studies and case series. Available evidence indicates that defibrotide is effective in the management of VOD/SOS. Using defibrotide prophylaxis should also be considered, especially in the paediatric setting, where there are available results from a large, open label, randomized controlled trial. Patient outcome data from the larger studies and compassionate programs can inform consensus recommendations on dosing regimen and criteria for the treatment of VOD/SOS with defibrotide in the adult population. The reviewed literature indicates an effective and safe dose for treatment is 25mg/kg/day, continued for at least 14days or until complete response is achieved. Further studies are required to determine the optimal dose and duration of treatment in both paediatric patients and adults. Recent recommendations and a phase 3 trial using historical controls indicate that defibrotide should be included as a pharmacotherapy option in protocols guiding management of VOD/SOS.

Failure to achieve therapeutic levels with high-dose posaconazole tablets potentially due to enhanced clearance

Aim To describe a case of persistent sub-therapeutic posaconazole levels in setting of salvage chemotherapy for relapsed acute myeloid leukemia. Case details A 57-year-old male was admitted for the management of relapsed acute myeloid leukemia and ongoing pulmonary aspergillosis. While continuing on posaconazole tablet 300 mg daily, he received a course of salvage chemotherapy. The initial steady state posaconazole trough level was therapeutic at 0.84 mg/L (target >0.70 mg/L). However, after five days, the level had dropped to 0.40 mg/L, coinciding with hyperbilirubinemia and hypoalbuminemia. Bilirubin level peaked at 36 µm/L (normal high <20 µm/L), albumin levels were consistently low, averaging at 25 g/L (range 33–46 g/L). The patient had been compliant and there were no underlying gastrointestinal conditions identified which might have potentially affected posaconazole absorption. Outcome An increase in posaconazole dose failed to achieve target levels and treatment was changed to voriconazole. However, levels were surprisingly supra-therapeutic, resulting in side effects and substantial dose reduction was required. Conclusion Failure to achieve target posaconazole levels despite increased dosing may be attributed to factors other than impaired oral absorption. Enhanced metabolism and clearance could be associated with hypoalbuminemia and hyperbilirubinemia. Further case studies, including PK modelling, are required to confirm this effect.