June M. McKoy

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia

CONTEXT The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs. OBJECTIVE To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer. DATA SOURCES A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008). STUDY SELECTION Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer. DATA EXTRACTION Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE. DATA SYNTHESIS Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20). CONCLUSIONS Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

Breakthrough zygomycosis after voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem-cell transplants or intensive chemotherapy

Zygomycosis is increasingly reported as a cause of life-threatening fungal infections. A higher proportion of cases reported over the last decades have been in cancer patients, with or without hematopoietic stem cell transplantation (HSCT). The new anti-fungal agent voriconazole is a recently identified risk factor for developing zygomycosis. We reviewed the clinical characteristics and outcomes of a large cohort of cancer patients who developed zygomycosis after exposure to voriconazole. Health care professionals at 13 large cancer centers provided clinical information on cancer patients with zygomycosis and prior exposure to voriconazole. Criteria for inclusion were 5 days or more of voriconazole use and diagnostic confirmation with tissue or histology. Fifty-eight cases were identified among patients with hematologic malignancies, 62% including patients who underwent a HSCT procedure. Fifty-six patients received voriconazole for primary or secondary prophylaxis against fungal infection. In addition to prior exposure to voriconazole, patients also had several of the previously established risk factors for zygomycosis. Amphotericin B was the most commonly prescribed anti-fungal therapy. Overall mortality was 73%. We conclude that zygomycosis after exposure to voriconazole is a recently described entity that is frequently fatal, despite treatment with currently available anti-fungal agents and surgery.

Epoetin-associated pure red cell aplasia: past, present, and future considerations.

BACKGROUND: Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin‐associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers.

Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project

Granulocyte-colony stimulating factor (G-CSF) is widely administered to donors who provide peripheral blood stem cells (PBSC) for individuals who undergo hematopoietic stem cell transplants. Questions have been raised about the safety of G-CSF in this setting. Herein, the Research on Adverse Drug Events and Reports (RADAR) project investigators reviewed the literature on G-CSF-associated adverse events in healthy individuals or persons with chronic neutropenia or cancer. Toxicities identified included bone pain and rare instances of splenic rupture, allergic reactions, flares of underlying autoimmune disorders, lung injury and vascular events. Among healthy individuals, four patients developed splenic rupture shortly after G-CSF administration and three patients developed acute myeloid leukemia 1 to 5 years after G-CSF administration. Registry studies identified no increased risks of malignancy among healthy individuals who received G-CSF before PBSC harvesting. However, more than 2000 donors would have to be followed for 10 years to detect a 10-fold increase in leukemia risk. Our review identifies bone pain as the most common toxicity of G-CSF administration. There are questions about a causal relationship between G-CSF administration and acute leukemia, but more long-term safety data from database registries are needed to adequately evaluate such a relationship.

Pharmacovigilance and reporting oversight in US FDA fast- track process: bisphosphonates and osteonecrosis of the jaw

More than half of all serious adverse reactions are identified 7 or more years after a drug receives approval from the US Food and Drug Administration (FDA). In 2002, 9 months after the intravenous bisphosphonate zoledronic acid received regulatory approval for marketing, the FDA received reports of nine patients with cancer, who were treated with zoledronic acid, who unexpectedly developed osteonecrosis of the jaw. During the next 2 years, three oral surgeons described 104 patients with cancer with osteonecrosis of the jaw in the medical literature and identified intravenous bisphosphonate therapy as being common to the care of these patients. In subspecialty medical, radiology, and dental journals, case reports and case series described clinical features of osteonecrosis of the jaw in patients with cancer who were treated with bisphosphonates. Manufacturer-sponsored epidemiological studies reported the first estimates of the incidence of this toxic effect, ranging from 0.1% to 1.8%. By contrast, independent epidemiological efforts from clinicians and the International Myeloma Foundation reported incidence estimates between 5% and 10%. Between 2003 and 2005, warnings about the risks of bisphosphonate-associated osteonecrosis were disseminated by national regulatory agencies, the manufacturers of bisphosphonates, and the International Myeloma Foundation. From 2006, independent clinical recommendations for diagnosis, prevention, and treatment of this toxic effect have been disseminated by manufacturers, national regulatory authorities, the International Myeloma Foundation, and medical specialty organisations. Furthermore, independent efforts by pharmaceutical manufacturers, dental and medical professionals, a non-profit organisation (the International Myeloma Foundation), patients, and regulatory authorities has led to the rapid identification and dissemination of safety information for this serious adverse reaction. Better coordination of safety-related pharmacovigilance initiatives is now needed.

Haematological malignancies developing in previously healthy individuals who received haematopoietic growth factors: Report from the Research on Adverse Drug Events and Reports (RADAR) project

Pegylated recombinant human megakaryocyte growth and development factor (PEG‐rHuMGDF) and granulocyte colony‐stimulating factor (G‐CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG‐rHuMGDF or G‐CSF administration. Information was reviewed for three of 538 volunteers who received PEG‐rHuMGDF in clinical trials and two of 200 donors who underwent G‐CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B‐cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1–5 years after PEG‐rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG‐rHuMGDF developed shortly after PEG‐rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G‐CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long‐term follow‐up among healthy individuals who receive haematopoietic growth factors is needed.

Clopidogrel-Associated TTP: An Update of Pharmacovigilance Efforts Conducted by Independent Researchers, Pharmaceutical Suppliers, and the Food and Drug Administration

Background and Purpose— Since the 1999 identification of clopidogrel-associated thrombotic thrombocytopenic purpura (TTP) through independent active surveillance, subsequent cases have been identified by pharmaceutical suppliers of clopidogrel and the Food and Drug Administration (FDA). For cases of clopidogrel-associated TTP reported between 1998 to 2002, we evaluated the quality and timeliness of data from 3 reporting systems-independent active surveillance (n=13), pharmaceutical suppliers (n=24), and the FDA (n=13)—and identified prognostic factors associated with mortality. Methods— This study assessed the completeness of information on TTP diagnosis, treatment response, and causality from the 3 reporting systems. In addition, predictors of mortality were identified through classification tree analysis. Results— Completeness, timeliness, and certainty of diagnosis were best for cases obtained by active surveillance, intermediate for cases reported to the pharmaceutical supplier, and poorest for cases reported directly to the FDA. Clopidogrel had been used for ≤2 weeks by 65%. The survival rate for patients with clopidogrel-associated TTP was 71.2%. Receipt of therapeutic plasma exchange within 3 days of onset of TTP increased the likelihood of survival (100% versus 27.3%, P <0.001). Conclusions— Compared with reports submitted by suppliers or the FDA, reports obtained through active surveillance provided timelier and more complete information. Clopidogrel-associated TTP often occurs within 2 weeks of drug initiation, occasionally relapses, and has a high mortality if not treated promptly.

A retrospective multicenter analysis of elderly Hodgkin lymphoma: outcomes and prognostic factors in the modern era

We investigated a recent (January 1999 to December 2009) cohort of 95 elderly Hodgkin lymphoma subjects. At diagnosis, median age was 67 years (range, 60-89 years), whereas 61% had significant comorbidity, 26% were unfit, 17% had a geriatric syndrome, and 13% had loss of activities of daily living. Overall response rate to therapy was 85%, whereas incidence of bleomycin lung toxicity was 32% (with associated mortality rate, 25%). With 66-month median follow-up, 2-year and 5-year overall survival were 73% and 58%, respectively (advanced-stage, 63% and 46%, respectively). Most International Prognostic Score factors were not prognostic on univariate analyses, whereas Cox multivariate regression identified 2 risk factors associated with inferior overall survival: (1) age more than 70 years (2.24; 95% CI, 1.16-4.33, P = .02) and (2) loss of activities of daily living (2.71; 95% CI, 1.07-6.84, P = .04). Furthermore, a novel survival model based on number of these risk factors (0, 1, or 2) showed differential 2-year OS of 83%, 70%, and 13%, respectively (P < .0001) and 5-year OS of 73%, 51%, and 0%, respectively (P < .0001).

Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

PURPOSE Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. METHODS We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. RESULTS Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. CONCLUSION AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989–2008)

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.