Anthony J. Perissinotti

Serum posaconazole levels among haematological cancer patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective analysis

The posaconazole extended release tablet formulation was developed to improve bioavailability relative to the oral suspension. Therapeutic drug monitoring has been used to optimise posaconazole dosing to achieve a target trough level ≥0.7 μg ml−1. We retrospectively evaluated 28 patients with haematological malignancies who received posaconazole tablets for antifungal prophylaxis. Posaconazole serum trough levels were obtained 5 days after initiation of therapy. Mean trough level was 1.19 ± 0.63 μg ml−1, and 71% achieved a trough level ≥0.7 μg ml−1. Diarrhoea was associated with lower mean trough levels (0.65 ± 0.08 μg ml−1 vs. 1.31 ± 0.13 μg ml−1), P = 0.002. Mean trough levels were lower in patients ≥90 kg (0.74 ± 0.09 μg ml−1) vs. <90 kg (1.32 ± 0.14 μg ml−1), P = 0.002 and in patients with body mass index (BMI) ≥30 (0.89 ± 0.13 μg ml−1) vs. BMI <30 (1.29 ± 0.14 μg ml−1), P = 0.05. Posaconazole delayed release tablets attain appropriate trough levels in most patients, but patients with a higher weight and those experiencing diarrhoea are more likely to have lower levels.

Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation

Objectives The association of posaconazole serum concentrations and toxicity is unclear. An assessment of whether levels obtained with the delayed-release tablet (DRT) formulation are correlated with abnormal liver function test (LFT) results and/or QTc prolongation was undertaken. Methods This was a multicentre, retrospective, observational study of adult patients with cancer between 26 November 2013 and 14 November 2014. Patients were included if they received posaconazole DRT with a posaconazole level obtained between days 5 and 14. Clinical data, including demographics, hepatotoxic medications, posaconazole levels, LFTs and QTc intervals, were obtained. Association of factors with changes in LFTs and QTc prolongation was assessed using linear and logistic regression. Results One hundred and sixty-six study patients were included. The median posaconazole level was 1250 (range 110-4220) ng/mL and the median time until level was 6 (range 5-14) days. There was a statistically significant increase in AST ( P  <   0.001), ALT ( P  <   0.001), alkaline phosphatase (ALK) ( P  <   0.001), total bilirubin (TBILI) ( P  <   0.001) and QTc ( P  =   0.05) from baseline. Posaconazole levels were not associated with increases in AST [β (SE) = -0.33 (2.2), P  =   0.88], log ALT [β (SE) = -0.02 (0.03), P  =   0.63], ALK [β (SE) = 2.2 (2.9), P  =   0.46] and TBILI [β (SE) = -0.01 (0.04), P  =   0.88]. For each additional hepatotoxic medication, there was a mean change in TBILI of 0.13 mg/dL ( P  =   0.02) and ALK of 7.1 U/L ( P  =   0.09). No statistically significant association between posaconazole level and QTc interval prolongation was found. Conclusions We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.

Pharmacokinetic and clinical considerations for monitoring asparaginase activity levels during pegaspargase therapy.

To the Editor: We read with interest the report by Bleyer et al. providing recommendations for therapeutic drug monitoring of asparaginase (ASNase) activity levels during treatment with pegaspargase [1]. Adequate asparagine depletion has been correlated with improved clinical outcomes and we applaud the authors’ initiative in developing and sharing a protocol for monitoring ASNase activity levels during pegaspargase therapy [2,3]. However, wewould like to comment on several parameters outlined in the proposed recommendation. The authors suggest a target ASNase activity level of 0.05 IU/ ml 4–7 days following pegaspargase treatment. However, based on in vivo pharmacokinetic/pharmacodynamic (PK/PD) models from the AALL07P4 trial and an analysis by Douer et al., a target level of >0.05 IU/ml is inadequate [4,5].With amean half-life of 5–7 days, PK/PD data suggests that on days 4–7, ASNase activity levels are typically between 0.6–1.2 IU/ml depending on the dose utilized and whether the dose is given during induction or consolidation [4,5]. Levels are near the higher end of this range with larger doses (e.g., 2500 IU/m) and during consolidation courses. More importantly, following pegaspargase treatment, asparagine repletion occurs when ASNase activity levels drop below 0.2–0.4 IU/ml [4,5]. This is in contrast to earlier data with native Escherichia coli ASNase in which asparagine repletion occurred when ASNase activity dropped below 0.1 IU/ml [6,7]. Using the proposed algorithm by Bleyer et al., a level of 0.1 on days 4–7 would prompt no change in therapy, yet at levels this low, asparagine is likely no longer depleted. With pegaspargase, the majority of patients’ ASNase activity levels do not drop below 0.2 IU/ml until day 21 [4,5]. A day 4–7 ASNase level which is already below 0.2 likely indicates the formation of neutralizing antibodies and should prompt clinicians to seriously consider switching to Erwinia asparaginase. Patients who have adequate levels on day 4–7 but low day 14–21 trough levels (<0.2) can be considered for a pegaspargase dose increase or interval decrease. The authors recommend testing ASNase activity for patients with clinical hypersensitivity and in those with prior exposure to ASNase, such as in the relapsed setting. However, there is little to no correlation between the formation of anti-ASNase antibodies and clinical hypersensitivity reactions [8]. Hypersensitivity does not always lead to antibody production, and antibody production can occur despite a lack of hypersensitivity. For example, in the CCG-1961 trial, 29% of patients without clinical hypersensitivity developed anti-ASNase antibodies and had a significantly higher relapse rate [8,9]. Thus, it is difficult to discern based upon clinical parameters which patients may benefit from monitoring ASNase activity levels. Testing ASNase activity solely in patients with clinical hypersensitivity or prior exposure may lead to overlooking patients who are at an increased risk of therapeutic failure associated with inadequate asparagine depletion. Due to the relatively low cost of ASNase activity testing compared with the cost of relapse, the clinical availability of the assay, and the strong correlation between asparagine depletion and improved survival, we believe ASNase activity levels should be monitored in all patients undergoing pegaspargase therapy.

Risk factors and impact of Clostridium difficile recurrence on haematology patients

Objectives The incidence of Clostridium difficile infection (CDI) in adults with malignancy is 7%-14% compared with 1%-2% in the general hospitalized population. Despite the increased incidence of CDI in this population, a major concern is the propensity of CDI to recur, leading to delays in therapy impacting outcomes. We conducted a retrospective case-control study to identify risk factors for recurrent CDI (rCDI) and to determine the impact of rCDI on adult patients with a haematological malignancy. Methods Adult haematology patients with CDI from June 2010 to December 2014 were divided into two groups: rCDI and non-rCDI. Multivariable models using logistic regression were constructed to identify risk factors for rCDI. Results A total of 100 patients in our study yielded a 41% recurrence rate. CDI impacted chemotherapy significantly more in the rCDI group (53.7% versus 11.9%, P  <0.001), primarily due to interruptions in established treatment plans (46.3% versus 10.3%, P  <0.001). Risk factors for rCDI identified at index included salvage lymphoma chemotherapy (OR 9.64, 95% CI 1.02-91.15, P  = 0.048) and severe CDI (OR 4.82, 95% CI 1.31-17.66, P  = 0.018). Longitudinal risk factors included exposure to fluoroquinolones (OR 3.96, 95% CI 1.04-15.15, P  = 0.044), ceftriaxone (OR 18.93, 95% CI 1.27-281.95, P  = 0.033) and piperacillin/tazobactam (OR 10.4, 95% CI 1.81-59.64, P  = 0.009). Conclusions Haematology patients exhibit a higher rate of rCDI than general hospitalized patients. Utilization of this multivariable model to guide index CDI therapy at index may help to decrease the rCDI and prevent delays or interruptions in chemotherapy.

Daptomycin nonsusceptible vancomycin resistant Enterococcus bloodstream infections in patients with hematological malignancies: risk factors and outcomes

Abstract Daptomycin is typically the treatment of choice for vancomycin resistant Enterococcus (VRE) bloodstream infections (BSI) in patients with hematological malignancies, but increasingly daptomycin nonsusceptible VRE are being reported. We reviewed our experience with daptomycin nonsusceptible VRE BSI among patients with hematological malignancies. We compared risk factors and outcomes of 20 patients with daptomycin nonsusceptible VRE BSI (case patients) with 40 matched control patients with daptomycin susceptible VRE BSI. Case patients had more complications (6/20 vs. 2/40, p = .013); all-cause mortality was similar in both groups. By multivariable analysis, only prior daptomycin exposure within 90 days was significantly associated with daptomycin nonsusceptible VRE BSI (odds ratio 26.71; p < .0001). In 25% of case patients, all of whose VRE isolates had an initial minimum inhibitory concentration (MIC) of 4 μg/mL, nonsusceptibility developed during treatment, raising the question of whether higher doses of daptomycin should be used for VRE BSI in hematology patients.

Catalyzing improvements in ALL therapy with asparaginase

Asparaginase remains a cornerstone of ALL therapy and is one of the key contributing factors to improved outcomes in adolescent and young adult (AYA) patients treated on pediatric protocols. Asparagine depletion has been associated with improved outcomes in ALL patients; this has led to an increased emphasis on optimizing asparagine depletion in ALL patients of all ages. To ensure adequate asparagine depletion, the use of therapeutic drug monitoring of asparaginase therapy holds much promise, yet remains underutilized in practice. Data regarding asparaginase activity level monitoring and associated outcomes are reviewed, and an evidence-based asparaginase activity level monitoring algorithm is presented. Finally, unique management strategies for key asparaginase toxicities in ALL patients are discussed, as well as a discussion of novel asparaginase formulations on the horizon.

PEGging down risk factors for peg-asparaginase hepatotoxicity in patients with acute lymphoblastic leukemia†

Abstract Asparaginase is commonly de-emphasized/omitted in adult acute lymphoblastic leukemia regimens due to poor tolerability, including hepatotoxicity (HTX). Adult patients (n = 100) given induction therapy containing pegylated asparaginase (PEG) from January 2008 to February 2016 were evaluated for HTX. Sixteen patients met criteria for HTX (direct bilirubin >3 g/dL). A multivariable model identified body surface area >2m2 (OR 7.40; 95% CI: 1.73–31.61, p = .007), albumin <3 mg/dL (OR 4.62; 95% CI: 1.09–19.68, p = .038), and platelet count <50 K/mm3 (OR 9.36; 95% CI: 2.13–41.17, p = .003) as risk factors for HTX. More patients with HTX missed ≥1 dose of intended chemotherapy (75% vs. 8%, p < .001). In patients with HTX, complete response and 30-day mortality rates were 40% and 9% versus 73% and 1% in patients without HTX (p = .02 and p < .001). A risk scoring tool was created to predict risk of toxicity, which should be validated through a prospective evaluation.

Risk factors for subtherapeutic levels of posaconazole tablet

Background Posaconazole is the prophylactic antifungal of choice for patients with haematological malignancies at high risk of invasive fungal infections (IFIs). Studies have demonstrated that subtherapeutic concentrations of posaconazole are associated with breakthrough fungal infections and specific risk factors for subtherapeutic troughs associated with the suspension formulation have been identified. However, these risk factors have not been evaluated in a large patient population with the recently approved tablet formulation. Objectives To determine the risk factors for subtherapeutic posaconazole troughs associated with the tablet formulation in patients receiving posaconazole as IFI prophylaxis. Patients and methods From 1 February 2013 to 31 March 2015 all posaconazole serum trough concentrations were evaluated. A total of 157 patients receiving posaconazole tablet for prophylaxis during induction therapy for haematological malignancies and allogeneic stem cell transplant recipients with graft-versus-host disease were included for analysis. Results Overall, 28 patients (18%) had subtherapeutic troughs (<700 ng/mL). Patients were more likely to have subtherapeutic troughs if they had diarrhoea (n = 24; 83%) (P < 0.001), were receiving a proton pump inhibitor (n = 27; 93%) (P = 0.016) and weighed >90 kg (n = 14; 48%) (P = 0.047). Conclusions While the posaconazole tablet has provided more consistent therapeutic concentrations when compared with the suspension there may still be a role for therapeutic drug monitoring (TDM). These results may guide us to a specific population in which TDM is necessary to identify subtherapeutic troughs.

Risk for Invasive Fungal Infections during Acute Myeloid Leukemia Induction Therapy: a True Association with Echinocandins?

We read the report by Gomes and colleagues characterizing the incidence of invasive fungal infections (IFIs) in patients with acute myeloid leukemia (AML) during remission induction chemotherapy ([1][1]). Given the high density of IFIs in the first 42 days after induction chemotherapy, as well as a

A review of CD19-targeted immunotherapies for relapsed or refractory acute lymphoblastic leukemia

Aim Novel immunotherapies have generated high response rates and unique adverse effects among patients with relapsed or refractory acute lymphoblastic leukemia. Therapies engaging endogenous T-cells against acute lymphoblastic leukemia are emerging for children and adults with various poor prognostic factors, thus accurate knowledge of immunotherapies is necessary for their effective implementation in the future. In this review, we evaluate clinical trial data regarding chimeric antigen receptor T-cells and blinatumomab, for the treatment of relapsed or refractory acute lymphoblastic leukemia. Summary In the relapsed or refractory setting, response rates rapidly diminish after subsequent lines of chemotherapy and cumulative toxicities may cause significant patient harm. Immunotherapies provide an approach to improve response rates and minimize traditional toxicities via novel mechanisms of action. Two therapies targeting CD19 antigens expressed on B-cell acute lymphoblastic leukemia lineages, chimeric antigen receptor T-cells, and blinatumomab have induced complete remissions among high-risk patient populations, especially those refractory to multiple therapies. Adverse effects such as cytokine release syndrome and neurologic sequelae remain serious precautions of each therapy. Conclusion Knowledge of immunotherapy mechanisms and clinical outcomes associated with immunotherapies is critical for the optimization of treating patients with relapsed or refractory acute lymphoblastic leukemia. Future use of chimeric antigen receptor T-cells and blinatumomab demands proper assessment of a patient’s disease and treatment history in addition to unique monitoring and supportive care interventions.