Erica Linden

Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation

Sirolimus is an effective agent used in graft-versus-host disease (GVHD) prophylaxis after allogeneic transplantation. It also has antiproliferative effects on vascular endothelium when used to coat coronary artery stents. We noted an excess of veno-occlusive disease (VOD) in a clinical trial, and retrospectively reviewed the records of 488 patients to determine the association between sirolimus and VOD. When used with cyclophosphamide/total body irradiation (Cy/TBI) conditioning, sirolimus is associated with an increased incidence of VOD (OR 2.35, P = .005). The concomitant use of methotrexate further increased this rate (OR 3.23, P < .001), while sirolimus without methotrexate was not associated with an increased risk of VOD (OR 1.55, P = .33). Mortality after VOD diagnosis was unaffected, and overall treatment-related mortality was lowest when sirolimus was used without methotrexate. Similar findings were noted in matched, related, and unrelated as well as mismatched donor subgroups. When used with busulfan-based conditioning, sirolimus use was associated with an even higher rate of VOD (OR 8.8, P = .008). Our findings suggest that sirolimus use is associated with VOD after TBI-based transplantation when used with methotrexate after transplantation. Sirolimus-based GVHD prophylaxis without methotrexate is associated with the greatest overall survival. Myeloablative doses of busulfan should not be used with sirolimus-based immunosuppression.

Targetable genetic features of primary testicular and primary central nervous system lymphomas

Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.

Lymphoma in Adolescents and Young Adults

Non-Hodgkin (NHL) and Hodgkin (HL) lymphomas are represented prominently in the adolescent and young adult (AYA) population. These diseases represent 11% of total cancer diagnoses in children, 4% in those 40 years of age and older, and 13% in AYA (aged 15-39 years). Although age-adjusted incidence rates of NHL increase with age, the more aggressive lymphomas are seen more commonly in the younger population with a transition to low-grade, indolent subtypes as the population ages. Burkitt lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, and anaplastic large cell lymphoma make up the most common subtypes in the AYA population, although within the subgroup age 30-39 years, follicular lymphoma becomes more prominent. As a result, much of the armamentarium in the treatment of aggressive NHL and HL in adults is based on data from pediatric clinical trials. There are obvious limitations to this approach. It is vital that we gain a more thorough understanding of the biology and therapeutic responsiveness of NHL and HL in the AYA population. Thus, we must leverage the large prospective and retrospective trials that have been completed to date and redirect our approaches to cancer care in this unique population. We review the epidemiological data on NHL and HL from the Surveillance, Epidemiology and End Results registries as a cornerstone for a comparative analysis of therapeutic outcomes available in this population.

Use of defibrotide in the treatment and prevention of veno-occlusive disease

Hepatic veno-occlusive disease (VOD) is one of the most important complications of high-dose chemotherapy and stem cell transplantation. VOD is a clinical syndrome characterized by jaundice, hepatic enlargement and fluid retention typically seen by day +30 after transplantation. Severe VOD is complicated by multiorgan failure and a high mortality rate approaching 100%. Defibrotide (DF) is a novel agent with both antithrombotic and fibrinolytic properties that has emerged as an effective therapy for severe VOD. In Phase II studies, treatment of severe VOD has resulted in complete responses of 30–60% and survival past day 100 ranging between 32–50%. A Phase III, historically controlled study of DF for treatment of severe VOD has recently been completed and results are awaited with interest. In addition, DF may be effective prophylaxis for VOD in high-risk patients. This review will focus on a summary of the pharmacology of DF and the clinical evidence for its use in VOD.

A Clinical Prediction Model to Assess Risk for Chemotherapy-Related Hospitalization in Patients Initiating Palliative Chemotherapy

IMPORTANCE Chemotherapy-related hospitalizations in patients with advanced cancer are common, distressing, and costly. Methods to identify patients at high risk of chemotherapy toxic effects will permit development of targeted strategies to prevent chemotherapy-related hospitalizations. OBJECTIVE To demonstrate the feasibility of using readily available clinical data to assess patient-specific risk of chemotherapy-related hospitalization. DESIGN, SETTING, AND PARTICIPANTS Nested case-control study conducted from January 2003 through December 2011 at the Mass General/North Shore Cancer Center, a community-based cancer center in northeastern Massachusetts. The parent cohort included 1579 consecutive patients with advanced solid-tumor cancer receiving palliative-intent chemotherapy. Case patients (n = 146) included all patients from the parent cohort who experienced a chemotherapy-related hospitalization. Controls (n = 292) were randomly selected from 1433 patients who did not experience a chemotherapy-related hospitalization. EXPOSURES Putative risk factors for chemotherapy-related hospitalization-including patient characteristics, treatment characteristics, and pretreatment laboratory values-were abstracted from medical records. Multivariable logistic regression was used to model the patient-specific risk of chemotherapy-related hospitalization. MAIN OUTCOMES AND MEASURES Chemotherapy-related hospitalization, as adjudicated by the oncology clinical care team within a systematic quality-assessment program. RESULTS A total of 146 (9.2%) of 1579 patients from the parent cohort experienced a chemotherapy-related hospitalization. In multivariate regression, 7 variables were significantly associated with chemotherapy-related hospitalization: age, Charlson comorbidity score, creatinine clearance, calcium level, below-normal white blood cell and/or platelet count, polychemotherapy (vs monotherapy), and receipt of camptothecin chemotherapy. The median predicted risk of chemotherapy-related hospitalization was 6.0% (interquartile range [IQR], 3.6%-11.4%) in control patients and 14.7% (IQR, 6.8%-22.5%) in case patients. The bootstrap-adjusted C statistic was 0.71 (95% CI, 0.66-0.75). At a risk threshold of 15%, the model exhibited a sensitivity of 49% (95% CI, 41%-57%) and a specificity of 85% (95% CI, 81%-89%) for predicting chemotherapy-related hospitalization. CONCLUSIONS AND RELEVANCE In patients initiating palliative chemotherapy for cancer, readily available clinical data were associated with the patient-specific risk of chemotherapy-related hospitalization. External validation and evaluation in the context of a clinical decision support tool are warranted.

Risk factors for the development of chemotherapy-related hospitalization (CRH) in patients treated with palliative intent: Results of a 9-year nested case control study.

3 Background: Palliative chemotherapy is aimed at improving quality of life and increasing life expectancy, without curative intent. Toxicity during palliative treatment defeats the goal of care and increases healthcare cost. We describe the predictors of CRHs among cancer patients treated for palliative intent at a community cancer center. METHODS We conducted a nested case-control study of adult cancer patients who received chemotherapy from Jan 03 to Dec 11. Utilizing a pharmacy database we identified patients who had received chemotherapy for palliative intent. For quality measures cancer center prospectively collects data on all the patients who developed CRH, which was used to identify cases. Hospitalizations were classified as CRH, disease-related or unrelated by a multidisciplinary panel. We frequency matched 2 controls to per case on lines of their chemotherapy treatment (3 groups). We obtained odds ratios (OR) and 95% confidence intervals (CI) from a multivariable logistic regression model on this set of 199 cases and 398 controls to identify predictors of CRH. A two-sided p-value of 0.05 was used for all measures of statistical significance. RESULTS During the selected period 6,850 patients received chemotherapy, 2,559 (37.3%) for palliative intent. 230 (9%) of 2,559 developed CRH. 76.5 % of CRH happened during the first 3 cycles of chemotherapy, and the mean length of stay was 5 days. Significant predictors on multivariable regression were ECOG score (p = .03), Charlson score (p= .0018), cancer site (p <.006,) abnormal creatinine (p <.0001) and low albumin (p < .007). CONCLUSIONS The results of this mature study demonstrate that patients treated with palliative chemotherapy have a substantial risk of severe hospital-requiring toxicity resulting in morbidity and cost. The finding that risk of severe toxicity is increased among patients with poor PS, multiple comorbidities and renal insufficiency suggests that some events may be avoidable. Furthermore, identified risk factors will enable the development and testing of a predictive model which could be used to identify patients at high risk of CRH prior treatment initiation.

Hepatic Veno-Occlusive Disease

The clinical syndrome of hepatic veno-occlusive disease (VOD) after hematopoietic stem cell transplantation (HSCT) is characterized by liver enlargement and pain, fluid retention, weight gain, and jaundice (1–3). Its onset is typically by d +30 after stem cell transplantation (SCT), although later onset has been described (4). As the diagnosis is based on clinical criteria, the incidence reported and severity seen is variable, ranging from 10% to 60%, and may be influenced by differences in conditioning regimens and patient characteristics (5,6). Prognosis is also variable. Mild disease is defined by no apparent adverse effect from liver dysfunction with complete resolution of symptoms and signs. Moderate disease is characterized by adverse effects of liver dysfunction requiring therapy such as diuresis for fluid retention and analgesia for right upper-quadrant pain but with eventual complete resolution. The majority of patients fall into the mild to moderate category, but a significant fraction of VOD is severe, and although occasional patients may recover, most are essentially incurable, with a fatality rate approaching 100% (5,7). VOD is considered to be part of the spectrum of nonmyeloid organ injury syndromes that can occur after high-dose therapy and SCT, which include idiopathic pneumonitis, diffuse alveolar hemorrhage, thrombotic microangiopathy, and capillary-leak syndrome. There is a growing body of evidence indicating that early injury to vascular endothelium either directly by the conditioning regimen or indirectly through the production of certain cytokines is a common denominator of these events (8–10). This may explain why VOD is more common in allogeneic SCT (a11oSCT), where there is a greater degree of cytokine dysregulation and immune dysfunction, as compared to autologous SCT (autoSCT) (5).