Bernard L. Marini

Role of T Cell TGFβ Signaling and IL-17 in Allograft Acceptance and Fibrosis Associated with Chronic Rejection

Chronic allograft rejection (CR) is the main barrier to long-term transplant survival. CR is a progressive disease defined by interstitial fibrosis, vascular neointimal development, and graft dysfunction. The underlying mechanisms responsible for CR remain poorly defined. TGFβ has been implicated in promoting fibrotic diseases including CR, but is beneficial in the transplant setting due to its immunosuppressive activity. To assess the requirement for T cell TGFβ signaling in allograft acceptance and the progression of CR, we used mice with abrogated T cell TGFβ signaling as allograft recipients. We compared responses from recipients that were transiently depleted of CD4+ cells (that develop CR and express intragraft TGFβ) with responses from mice that received anti-CD40L mAb therapy (that do not develop CR and do not express intragraft TGFβ). Allograft acceptance and suppression of graft-reactive T and B cells were independent of T cell TGFβ signaling in mice treated with anti-CD40L mAb. In recipients transiently depleted of CD4+ T cells, T cell TGFβ signaling was required for the development of fibrosis associated with CR, long-term graft acceptance, and suppression of graft-reactive T and B cell responses. Furthermore, IL-17 was identified as a critical element in TGFβ-driven allograft fibrosis. Thus, IL-17 may provide a therapeutic target for preventing graft fibrosis, a measure of CR, while sparing the immunosuppressive activity of TGFβ.

Risk factors for recurrent Clostridium difficile infection in hematopoietic stem cell transplant recipients

Recurrent Clostridium difficile infection (CDI) represents a significant burden on the healthcare system and is associated with poor outcomes in hematopoietic stem cell transplant (HSCT) patients. Data are limited evaluating recurrence rates and risk factors for recurrence in HSCT patients.

The effects of an informational video on patient knowledge, satisfaction and compliance with venous thromboembolism prophylaxis: A pilot study

OBJECTIVE Venous thromboembolism (VTE) is the leading cause of preventable death in hospitalized patients. Educational videos have been effectively used to increase patient satisfaction and knowledge. This study examined possible benefits of an educational video about VTE. METHODS Medical patients receiving VTE prophylaxis were screened within 48 h of admission. Upon enrollment, patients were randomly assigned to either watch a 5 min educational video on VTE or not, in addition to standard VTE education. Within 24-48 h after randomization, all patients completed a survey assessing VTE prophylaxis knowledge and satisfaction. RESULTS Patients who watched the video averaged 83% correct responses to knowledge-based questions (regarding VTE risk, symptoms, and preventative measures) versus an average score of 62% for patients in the no video group (p<0.001). Patients who watched the video were more satisfied with their VTE education (4.8 vs. 3.4 out of 5, p<0.001). CONCLUSION This educational video effectively provided baseline information to patients about VTE and improved patient satisfaction. PRACTICE IMPLICATIONS A VTE educational video can be an effective tool for improving patient knowledge of the condition.

Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma

Pediatric high-grade glioma (HGG, WHO Grade III and IV) is a devastating brain tumor with a median survival of less than two years. PDGFRA is frequently mutated/amplified in pediatric HGG, but the significance of this finding has not been fully characterized. We hypothesize that alterations of PDGFRA will promote distinct prognostic and treatment implications in pediatric HGG. In order to characterize the impact of PDGFR pathway alterations, we integrated genomic data from pediatric HGG patients (n=290) from multiple pediatric datasets and sequencing platforms. Integration of multiple human datasets showed that PDGFRA mutation, but not amplification, was associated with older age in pediatric HGG (P= <0.0001). In multivariate analysis, PDGFRA mutation was correlated with worse prognosis (P = 0.026), while PDGFRA amplification was not (P = 0.11). By Kaplan-Meier analysis, non-brainstem HGG with PDGFRA amplification carried a worse prognosis than non-brainstem HGG without PDGFRA amplification (P = 0.021). There were no pediatric patients with PDGFRA-amplified HGG that survived longer than two years. Additionally, we performed paired molecular profiling (germline / tumor / primary cell culture) and targeting of an infant thalamic HGG with amplification and outlier increased expression of PDGFRA. Dasatinib inhibited proliferation most effectively. In summary, integration of the largest genomic dataset of pediatric HGG to date, allowed us to highlight that PDGFRA mutation is found in older pediatric patients and that PDGFRA amplification is prognostic in non-brainstem HGG. Future precision-medicine based clinical trials for pediatric patients with PDGFRA-altered HGG should consider the optimized delivery of dasatinib.

Treatment of Dyslipidemia in Allogeneic Hematopoietic Stem Cell Transplant Patients

As survival rates in allogeneic hematopoietic stem cell transplantation (HSCT) continue to improve, attention to long-term complications, including cardiovascular disease, becomes a major concern. Cardiovascular disease and dyslipidemia are a common, yet often overlooked occurrence post-HSCT that results in significant morbidity and mortality. Also, increasing evidence shows that several anti-hyperlipidemia medications, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in particular, may have a role in modulating graft-versus-host disease (GVHD). However, factors such as drug-drug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into account when choosing safe and effective lipid-lowering therapy in this setting. This review seeks to provide guidance to the clinician in the management of dyslipidemia in the allogeneic HSCT population, taking into account the recently published American College of Cardiology/American Heart Association guidelines on hyperlipidemia management, special considerations in this challenging population, and the evidence for each agents potential role in modulating GVHD.

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.