Secondary Hemophagocytic Lymphohistiocytosis in Adults: An Update on Diagnosis and Therapy

Abstract: Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome (HPS), is a rare, life-threatening, hematologic disorder manifested by clinical findings of extreme inflammation and unregulated immune activation. In both its congenital (primary) and adult (secondary) forms, it is most often characterized by fevers, hepatomegaly or splenomegaly, and bi- or trilineage cytopenias. In addition, elevated liver enzymes, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia are commonly seen in HLH patients. A high index of suspicion is necessary for early diagnosis. Furthermore, a thorough diagnostic evaluation is necessary, and prompt treatment of the underlying causes is key in order to prevent irreversible tissue damage. Here we discuss the clinical signs, diagnosis, and treatments associated with this rare and potentially lethal disorder as manifested in adults.

Treatment of Primary Systemic Amyloidosis (AL): Role of Intensive and Standard Therapy

Immunoglobulin light-chain (AL) amyloidosis is a clonal plasma cell dyscrasia. Delay in diagnosis is the major hurdle in improving the outcomes of AL patients. Almost all patients with systemic AL need cytotoxic therapy. Treatment can improve symptoms and quality of life, as well as extend survival. Supportive care is an integral part of the treatment plan. Severity of cardiac involvement is an important determinant of prognosis and influences the choice of therapy. Cardiac biomarkers and serum free light chain assay are important tools for assessing prognosis and monitoring treatment response. Myeloablative chemotherapy with melphalan and autologous stem cell rescue appears to offer survival benefit; however, it is an option for only a quarter of AL patients. Standard-dose combination chemotherapy with steroids and alkylating agents is a safe and effective treatment strategy that can result in improvement of organ function in many patients. Newer agents such as bortezomib and lenalidomide have shown promising activity and are being evaluated as part of combination regimens in clinical trials.

To Transplant or Not to Transplant  for Adult Acute Myeloid Leukemia: An Ever-Evolving Decision

In 2007, a group of experts charged by the American Society for Blood and Marrow Transplantation critically reviewed the available literature and summarized the indications for allogeneic hematopoietic cell transplantation versus chemotherapy in adults with acute myeloid leukemia. Much of the resulting position statement was based on studies conducted nearly 2 decades ago, and may not accurately represent current treatment. As a result of advances in both therapeutic regimens and supportive care, a number of recent studies have demonstrated clear and consistent improvements in the outcomes of patients receiving chemotherapy and allogeneic hematopoietic cell transplantation. In addition, prognostic accuracy has improved with the identification of mutations not detected by traditional cytogenetics. With these advancements in prognostic accuracy and treatment, it is now appropriate to revisit the indications for transplantation versus chemotherapy.

Highlights From the 2012 ASCO Breast Cancer Symposium

98 Primary Results From EMILIA, a Phase III Study of Trastuzumab Emtansine (T-DM1) Versus Capecitabine (X) and Lapatinib (L) in HER2-Positive Locally Advanced or Metastatic Breast […]

Skin Cancer in Patients With Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma

The association between non-Hodgkin lymphoma, including chronic lymphocytic leukemia, and aggressive skin cancers is well established. This review highlights existing data that address increased incidence and clinical characteristics of skin cancers in patients with non-Hodgkin lymphoma—specifically, chronic lymphocytic leukemia. Patients with non-Hodgkin lymphoma have worse outcomes when melanoma and nonmelanoma skin cancers develop. The poorer outcomes in these patients are evidenced by increased rates of local recurrence, regional metastasis, and death. Lymphoproliferative neoplasms and certain skin cancers may share similar pathogenic factors, which could provide insights regarding their close relationship and the behavior of lymphoma-related skin cancers. As a consequence of the poorer prognosis in patients with lymphoma-related skin cancer, more aggressive therapeutic measures could reduce the risk of skin cancer recurrence, metastasis, and death. Strategies such as sun protection, education, and frequent dermatologic examinations may help prevent and successfully treat skin cancers in patients with lymphoma.

Clinical Trials of Bisphosphonates in Multiple Myeloma

More than 80% of patients with multiple myeloma (MM) have osteolytic bone disease, which increases the risk of skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, and the need for radiotherapy or surgery. Bone disease is primarily due to increased osteoclastic activity and impaired osteoblast activity. Bisphosphonates are pyrophosphate analogues with high bone affinity that can inhibit osteoclastic activity. Pamidronate and zoledronic acid are the most commonly used bisphosphonates in multiple myeloma. Other agents include ibandronate and clodronate. Bisphosphonates are associated with several adverse events, such as renal toxicity and osteonecrosis of the jaw. The optimal duration of bisphosphonate therapy has yet to be determined. Clinical trials are investigating tailored approaches to management based on treatment-related changes in levels of bone resorption markers.

Novel Agents in Invasive Urothelial Cancer

Invasive urothelial cancer is an aggressive, biologically heterogeneous disease. Most patients present with non–muscle invasive bladder cancer involving the epithelium as exophytic tumors, in situ carcinoma, or minimally invasive disease involving the lamina propria. Such patients are typically managed with complete transurethral resection with or without intravesical therapy. Muscle invasive urothelial cancer, however, is biologically and clinically distinct. This subtype is characterized by mutations or deletions in tumor suppressor genes, such as TP53, Rb, and PTEN, leading to genomic instability and a more aggressive phenotype. Survival in advanced disease is poor with currently available treatment strategies. Technological advances in the ability to molecularly characterize human cancer have led to the identification of genetic alterations that may be therapeutically exploitable. Novel chemotherapies, such as antifolates and taxanes, have shown promise in urothelial cancer. Agents against novel molecular targets, such as the human epidermal receptor (HER) and vascular endothelial growth factor receptor (VEGFR), are being investigated. This review article focuses on the current status of novel chemotherapeutic and targeted agents as well as immunotherapy currently in clinical development in invasive urothelial cancer.

Cancer of Unknown Primary Site: Evolving Understanding and Management of Patients

Cancer of unknown primary site is a common clinicopathologic syndrome representing a very heterogeneous group of patients with metastatic cancers and clinically undetectable primary tumor sites. The standard treatment for these patients for the last 15 years has been empiric “broad-spectrum” chemotherapy. In recent years, improved immunocytochemistry and the emergence of gene expression profiling have provided the diagnostic tools necessary to accurately define the tissue of origin in the majority of patients. Recent data have confirmed the ability of molecular profiling assays to complement standard pathologic diagnosis, and a large prospective study has documented a survival improvement for patients treated with site-specific therapy directed by the molecular assay diagnoses of their tissues of origin compared to empiric chemotherapy. The clinicopathologic evaluation of patients is now more standardized. The era of empiric chemotherapy administered to all patients is coming to an end, and customized therapies are favored. The management of patients has evolved with the ability to confidently define the tissue of origin. Further delineation of the molecular aberrations in advanced solid tumors, regardless of the primary tumor site, signals a more precise and perhaps more effective therapy for each patient.

A Phase II Trial of Preoperative Concurrent Chemotherapy/Radiation Therapy Plus Bevacizumab/Erlotinib in the Treatment of Localized Esophageal Cancer

Purpose: To evaluate the efficacy of bevacizumab (Avastin, Genentech) and erlotinib (Tarceva, Genentech/Roche) when added to preoperative chemoradiation therapy with paclitaxel, carboplatin, and infusional 5-fluorouracil (5-FU) in the treatment of localized cancers of the esophagus or gastroesophageal (GE) junction. The primary endpoint was the pathologic complete response (pCR) rate. Methods: Eligible patients had previously untreated localized squamous cell, adenocarcinoma, or adenosquamous carcinoma of the esophagus or GE junction, and were considered surgical candidates at enrollment. Daily erlotinib (100 mg orally) was administered on days 1–42 of preoperative treatment. Patients received paclitaxel (200 mg/m2 intravenously [IV]), carboplatin (area under the curve [AUC] 5.0 IV), and bevacizumab (15 mg/kg IV) on days 1 and 22, and 5-FU by continuous infusion (225 mg/m2/day IV) on days 1–35, with radiation therapy in 1.8-Gy single fractions, Monday–Friday (to a total of 45 Gy). Those who were deemed surgical candidates proceeded to resection during weeks 12–14. Results: Between February 2007 and September 2009, 62 patients (median age, 64 years; 92% male; 94% adenocarcinoma) were enrolled; 44 patients (71%) completed neoadjuvant treatment and proceeded to surgery. Eighteen patients (29%) achieved pCR, with partial pathologic remission in an additional 22 patients (35%). Common grade 3/4 toxicities included leukopenia (64%), neutropenia (44%), mucositis/stomatitis (42%), diarrhea (27%), and esophagitis (27%). There were 40 instances of treatment-related hospitalization, and 2 postoperative deaths. Conclusions: The addition of bevacizumab and erlotinib to neoadjuvant chemoradiation did not demonstrate survival benefit or improved pCR rate over similar regimens. While the overall rates of toxicity were not increased, targeted agent–specific toxicity was evident. Further study of this specific regimen is not warranted.

Systemic Therapy of Advanced Pancreatic Cancer: Has the Landscape Changed?

Limited progress has been made in the treatment of advanced pancreatic cancer. Gemcitabine was established as a standard of care after a randomized phase III study showed an improvement in clinical benefit response and overall survival over 5-flurouracil. Multiple phase III studies have been conducted to improve upon the response and survival established with single-agent gemcitabine. Combining different cytotoxic chemotherapy with gemcitabine failed to provide any meaningful survival advantage over gemcitabine monotherapy. A modest improvement in overall survival was noted when an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib) was added to gemcitabine. The landscape for the treatment of advanced pancreatic cancer changed with the introduction of the fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) regimen at the 2010 American Society of Clinical Oncology meeting. The phase III clinical trial showed an overall survival improvement in the gemcitabine group of 6.8 months compared to 11.1 months in the FOLFIRINOX arm (P<.0001). More interestingly, almost half of the patients in the FOLFIRINOX group were alive after 1 year, and the response rate was 31.6%. A new triplet chemotherapy regimen has emerged to replace the use of single-agent gemcitabine in a highly selected patient population. In this article, we will review the published data on first-line chemotherapy, with discussion of targeted agents for advanced pancreatic cancer and potential future directions.

Prevalence of Iron Overload in Pediatric Oncology Patients After Blood Transfusion

Background: Studies evaluating the prevalence of iron overload and its relationship to blood transfusion in pediatric oncology patients are limited. Methods: Medical records of all pediatric oncology patients treated at Roger Maris Cancer Center (Fargo, North Dakota) were screened. Subjects with measurements of serum ferritin levels after completion of therapy (N=52) were further evaluated. Results: Of the total study population, 37 patients (71.2%) underwent red blood cell (RBC) transfusion and 15 patients (28.8%) did not. Among the transfused patients, 20 patients (54%) had elevated serum ferritin values greater than 250 ng/mL. Among the patients who did not undergo blood transfusion, only 1 patient (6.6%) had an elevated serum ferritin value (P<.01; Fischer exact test). None of the nontransfused patients had ferritin levels greater than 501 ng/mL. Conclusion: This study demonstrated that ferritin levels were more likely to be elevated in transfused patients than nontransfused patients. The number of subjects in this study was limited, and further prospective studies are needed.

Hepatitis B Reactivation in Cancer Patients: Role of Prechemotherapy Screening and Antiviral Prophylaxis

Hepatitis B virus (HBV) infection is a potentially life-threatening condition that can be effectively prevented by vaccination. In the United States, more than 1.5 million people are infected with HBV, and that number continues to rise with the arrival of immigrants from HBV-endemic countries.Cancer is the second leading cause of death in the United States; 1 in 2 men and women will be diagnosed during their lifetime, and a large proportion of them will require chemotherapy. Chemotherapy-induced immunosuppression can result in HBV reactivation in asymptomatic HBV carriers or patients with resolved HBV infection, causing severe morbidity and mortality. The rate of HBV reactivation depends on several factors, including host and viral factors, and varies from 3–88%. Mortality rates in HBV reactivation range from 23–71%. However, a recent US survey showed that 20% of practicing oncologists never perform any type of HBV screening before the initiation of chemotherapy, and less than 40% perform HBV screening in patients who have high-risk factors for HBV or a history of hepatitis. Given the magnitude of this clinical problem, it is very important to increase awareness among physicians regarding this potentially life-threatening complication. In this article, we review the current understanding of the problem, discuss the existing guidelines from professional societies, and outline a management plan.

Management of Glioblastoma in the Elderly

The optimal management of elderly patients with glioblastoma multiforme (GBM) remains controversial, as no evidence-based standard of care exists for this unique subpopulation. These patients typically have a poor prognosis and high rates of treatment-related toxicities. Unfortunately, many elderly GBM patients are often excluded from clinical trials. Consequently, the role of chemoradiotherapy with temozolomide for elderly patients is unclear, and these patients are often treated with radiotherapy (RT) alone or palliative approaches following surgical diagnosis. However, there is emerging evidence that healthy and fit elderly patients may benefit from combined modality therapy, and aggressive therapy should be considered. Elderly patients with poor performance scores have historically been offered RT alone when treated, but preliminary data support the use of temozolomide as initial therapy. Moreover, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation appears to be a predictive marker of benefit from temozolomide. In the future, this molecular prognostic factor may be used clinically to guide therapeutic decision-making for some elderly GBM patients. Nevertheless, other factors that affect quality of life, such as number of trips to the hospital, number of ancillary tests, morbidity of treatment, and treatment costs to the patient and community should also be considered.

Comprehensive Overview of Axitinib Development in Solid Malignancies: Focus on Metastatic Renal Cell Carcinoma

The landscape of treatment for metastatic renal cell carcinoma (mRCC) continues to evolve. Although several new drugs have been approved for the treatment of this disease in recent years, mRCC remains incurable. Thus, the search continues for new effective therapies. One such novel compound is axitinib (Inlyta, Pfizer), a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor. Following phase I testing in advanced solid tumors (where hypertension, stomatitis, and diarrhea were the dose-limiting toxicities), use of axitinib has been further developed through phase II testing in thyroid, breast, lung, and renal cancers. Recently, the phase III AXIS (Axitinib [AG 013736] as Second Line Therapy for Metastatic Renal Cell Cancer) trial demonstrated an improvement in progression-free survival for patients with mRCC who were treated with axitinib versus sorafenib (Nexavar, Bayer) as second-line therapy. This article describes the preclinical and clinical evolution of axitinib, with an emphasis on its development and role in mRCC.

The Role of the Fallopian Tube in Ovarian Cancer

High-grade serous carcinoma (HGSC) is the most common and lethal subtype of ovarian cancer. Research over the past decade has strongly suggested that “ovarian” HGSC arises in the epithelium of the distal fallopian tube, with serous tubal intraepithelial carcinomas (STICs) being detected in 5–10% of BRCA1/2 mutation carriers undergoing risk-reducing surgery and up to 60% of unselected women with pelvic HGSC. The natural history, clinical significance, and prevalence of STICs in the general population (ie, women without cancer and not at an increased genetic risk) are incompletely understood, but anecdotal evidence suggests that these lesions have the ability to shed cells with metastatic potential into the peritoneal cavity very early on. Removal of the fallopian tube (salpingectomy) in both the average and high-risk populations could therefore prevent HGSC, by eliminating the site of initiation and interrupting spread of potentially cancerous cells to the ovarian/peritoneal surfaces. Salpingectomy may also reduce the incidence of the 2 next most common subtypes, endometrioid and clear cell carcinoma, by blocking the passageway linking the lower genital tract to the peritoneal cavity that enables ascension of endometrium and factors that induce local inflammation. The implementation of salpingectomy therefore promises to significantly impact ovarian cancer incidence and outcomes.

Metastatic Non–Small Cell Lung Cancer Management: Novel Targets and Recent Clinical Advances

Lung cancer continues to be the most common cause of cancer-related mortality in the United States and other developed countries. The most common subtype is non–small cell lung cancer (NSCLC). Within NSCLC, we are discovering remarkable molecular heterogeneity. Most current actionable mutations have been identified in patients with adenocarcinoma histology, but now new mutations are being discovered in squamous cell histology patients as well. This molecular heterogeneity provides an opportunity for clinical trials to exploit various candidate oncogene-addicted pathways in NSCLC. This article focuses on 2 shifting paradigms in NSCLC management: the recent advances in targeted therapy and maintenance treatment.

Phase II Study of Concurrent Radiation Therapy, Temozolomide, and Bevacizumab Followed by Bevacizumab/Everolimus as First-Line Treatment for Patients With Glioblastoma

Purpose: To evaluate the efficacy of adding bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, and everolimus, a mammalian target of rapamycin (mTOR inhibitor), to standard radiation therapy/temozolomide in the first-line treatment of patients with glioblastoma. Patients and methods: Following surgical resection or biopsy, patients with newly diagnosed glioblastoma received standard radiation therapy/temozolomide plus bevacizumab 10 mg/kg intravenously (IV) every 2 weeks. Four weeks after the completion of radiation therapy, patients began oral everolimus 10 mg daily, and continued bevacizumab every 2 weeks; therapy continued until tumor progression or unacceptable toxicity. Results: Sixty-eight patients were treated, 82% of whom had previously undergone partial or complete surgical resection. Sixty-four patients completed combined modality therapy, and 57 patients began maintenance therapy with bevacizumab/everolimus. Thirty-one of 51 patients (61%) with measurable tumor had objective responses. After a median follow-up of 17 months, the median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 9.3–13.1 months); median overall survival was 13.9 months. Toxicity was consistent with the known toxicity profile of bevacizumab; grade 3/4 toxicities during maintenance therapy related to everolimus included fatigue (27%), pneumonitis (7%), and stomatitis (5%). Conclusions: The use of bevacizumab and everolimus as part of first-line combined modality therapy for glioblastoma was feasible and efficacious. The PFS compared favorably to previous reports with standard radiation therapy/temozolomide therapy, and is similar to results achieved in other phase II trials in which bevacizumab was added to fist-line treatment. Ongoing randomized phase III trials will clarify the role of bevacizumab in this setting.

Radon and Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Radon exposure is the second leading cause of lung cancer, following tobacco smoke. Radon is not only an independent risk factor; it also increases the risk of lung cancer in smokers. Numerous cohort, case-control, and experimental studies have established the carcinogenic potential of radon. The possibility of radon having a causative effect on other cancers has been explored but not yet proven. One of the postulated mechanisms of carcinogenesis is DNA damage by alpha particles mediated by the production of reactive oxygen species. The latter are also thought to constitute one of the common mechanisms underlying the synergistic effect of radon and tobacco smoke. With an estimated 21,000 lung cancer deaths attributable to radon in the United States annually, the need for radon mitigation is well acknowledged. The Environmental Protection Agency (EPA) has established an indoor limit of 4 picocuries (pCi)/L, and various methods are available for indoor radon reduction when testing shows higher levels. Radon mitigation should accompany smoking cessation measures in lung cancer prevention efforts.

Advances in the Systemic Treatment of Leptomeningeal Cancer

Leptomeningeal cancer (LMC), which refers to involvement of the cerebrospinal fluid by cancer cells, is a poor prognostic sign that complicates various solid malignancies. Treatment of LMC evolved around brain radiation, intrathecal therapy, and systemic chemotherapy, but response rates are unsatisfactory, and patients usually die from cancer progression. In this article, we review the history of the major therapeutic approaches used to treat LMC, and we expand on the promising new venues for applying biologic targeted agents to the treatment options utilized in LMC.

Chemotherapy and Immunotherapy Combination in Advanced Prostate Cancer

In prostate cancer, there is considerable evidence that tumors promote immune tolerance starting early in the disease. By suppressing tumors and activating immune system homeostatic mechanisms, chemotherapy may help overcome this tumor-induced immune tolerance. As such, chemotherapy may therefore support improved results from novel immune-modulating therapies. Prostate cancer is particularly suited for active immunotherapy because prostate tumor cells express a number of distinctive surface antigens. Sipuleucel-T, which has recently been approved in the United States, is an active immunotherapy that triggers T-cell responses against prostate cancer. An exploratory analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, VITAL-2, a phase III trial investigating a prostate cancer therapeutic vaccine plus concurrent docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed lower overall survival with the vaccine regimen. This trial highlights major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy. Patient characteristics, prostate cancer disease stage, and treatment history also may influence the response to combined therapy. Advances in biomarker validation and trial design are needed to efficiently investigate these issues.