David L. DeRemer

Nilotinib: A second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia

BACKGROUND Nilotinib, a second-generation tyrosine kinase inhibitor (TKI) formerly known as AMN107, was approved by the US Food and Drug Administration (FDA) on October 29, 2007, for the treatment of adult patients with chronic-phase (CP) and accelerated-phase (AP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) resistant to or intolerant of prior treatment that included imatinib. OBJECTIVE The purpose of this review was to evaluate the pharmacology, pharmacokinetic properties, and pharmacodynamic properties of nilotinib; results of clinical trials in patients with CML, Ph+ acute lymphoblastic leukemia (ALL), and gastrointestinal stromal tumors (GISTs); and potential drug interactions. METHODS Literature was identified and reviewed using searches of MEDLINE (1966-April 1, 2008), the American Society of Hematology and American Society of Clinical Oncology abstracts databases (2002-2008 annual meetings/symposia), the European Hematology Association abstracts database (2006-2007 annual meetings), and the American Association for Cancer Research symposia (2000-2007). Search terms included, but were not limited to, nilotinib, AMN107, chronic myelogenous leukemia, acute lymphoblastic leukemia, bcr-abl, imatinib resistance, adverse events, pharmacology, and clinical trials. RESULTS Nilotinib is an orally bioavailable derivative of imatinib with improved specificity toward the breakpoint cluster region-Abelson murine leukemia (bcr-abl) viral protooncogene. In preclinical studies, nilotinib was found to have activity against 32 of 33 imatinib-resistant bcr-abl mutations, but not against the T3151 mutation. On pharmacokinetic analysis, T(max) was 3 hours. The calculated t((1/2)) following multiple daily dosing was approximately 17 hours. The main metabolic pathways identified were oxidation and hydroxylation. The parent compound is the circulating component found in serum; the metabolites were not found to contribute to pharmacologic activity. Nilotinib is a competitive inhibitor of cytochrome P450 (CYP) 3A4, CYP2C8, CYP2C9, and CYP2D6. In 2 Phase II, open-label, single-arm clinical studies, nilotinib was found to be beneficial in patients with CML that was imatinib resistant or intolerant. Overall, 58% of patients with CML-CP achieved a major cytogenetic response; 42%, a complete cytogenetic response; and 77%, a complete hematologic response (CHR). At 18 months, the estimated overall survival rate was 91%. Of patients whose disease had progressed to AP, nilotinib was associated with major cytogenetic response in 32%; complete cytogenetic response in 19%; and CHR in 30%. At 12 months, an estimated 56% of patients lacked progression of disease, and the estimated overall survival rate was 82%. Concurrent use of CYP3A4 inhibitors should be avoided. The most common toxicities attributable to nilotinib include rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, and vomiting. Grade 3/4 toxicities (> or = 10%) have included thrombocytopenia, neutropenia, elevated lipase, hyperglycemia, and hypophosphatemia. Nilotinib has been associated with a prolonged QT interval, and sudden death has been reported. The FDA-approved regimen of nilotinib is 400 mg PO BID on an empty stomach. CONCLUSIONS Nilotinib is an oral second-generation bcr-abl TKI indicated for the treatment of imatinib resistant or -intolerant Ph+ CML-CP and -AP in adults. Positive clinical activity and tolerability have been reported in clinical trials. Clinical data on off-label indications and in patients with Ph+ ALL and GIST continue to emerge.

Antiangiogenic Therapy for Cancer: An Update

The idea of antiangiogenic therapy was the brainchild of Dr. Judah Folkman in the early 1970s. He proposed that by cutting off the blood supply, cancer cells would be deprived of nutrients and, hence, treated. His efforts paid off when bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, was approved as antiangiogenic therapy in 2004 for the treatment of colon cancer. Since then, an array of antiangiogenic inhibitors, either as monotherapy or in combination with other cytotoxic and chemotherapy drugs, have been developed, used in clinical trials, and approved for the treatment of cancer. Despite this important breakthrough, antiangiogenic therapy for cancer met with a number of hurdles on its way to becoming an option for cancer therapy. In this article, we summarize the most current information on the mechanisms of tumor angiogenesis, proangiogenic and antiangiogenic factors, potential targets and their mechanisms of action, and experimental evidences, as well as the most recent clinical trial data on antiangiogenic agents for cancer therapy.

Tyrosine kinase inhibitors in the treatment of systemic mastocytosis

Systemic mastocytosis (SM) is a heterogeneous disease, vast majority of these patients have a gain of function mutation in the gene encoding the tyrosine kinase KIT (KIT(D816V)). A small subset of SM patients with KIT(D816V) mutation require cytoreductive therapy. In these patients, tyrosine kinase inhibitors (TKIs) have been actively investigated over the last decade because of codon 816 KIT mutations causing constitutive activation of tyrosine kinase activity of the molecule. The main question has been whether the success story with imatinib in chronic myeloid leukemia (CML), another disease associated with a constitutively active tyrosine kinase, could be mimicked in mastocytosis. However, the results from various TKIs in SM with KIT(D816V) mutation have been disappointing to date. Only a few of the TKIs sufficiently block KIT(D816V) activity and have shown promising clinical results. The data from these studies indicate that, apart from KIT(D816V), other kinase targets and target pathways may play a role in disease evolution and progression, especially in patients with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Imatinib is effective in patients with increased mast cells and eosinophils associated with FIP1L1/PDGFRA+ (e.g., myeloid neoplasm with eosinophilia and rearrangement of PDGFRA) or rare patients with SM associated with KIT mutations outside of exon 17. This review will focus on the KIT receptor, KIT mutations, and the effects of the mutations in SM. The preclinical and clinical activities of FDA approved TKIs (for CML) as well as novel TKIs in SM will be evaluated.

Angiotensin receptor blockers and angiogenesis: clinical and experimental evidence

Angiotensin II type 1 receptor antagonists [ARBs (angiotensin receptor blockers)] are indicated for BP (blood pressure)-lowering, renal protection and cardioprotection in patients unable to tolerate ACEIs (angiotensin-converting enzyme inhibitors). A recent meta-analysis revealed an association between ARBs and tumour development, possibly due to enhancement of angiogenesis. However, published evidence is conflicting on the effects of ARBs on angiogenesis or the expansion of the existing vascular network. ARBs have been shown to exert primarily anti-angiogenic effects in basic science studies of cancer, retinopathy, peripheral artery disease and some models of cardiovascular disease. In animal and cellular models of myocardial infarction and stroke, however, ARB administration has been associated with robust increases in vascular density and improved recovery. The aim of the present review is to examine the angiogenic effects of ARBs in animal and cellular models of relevant disease states, including proposed molecular mechanisms of action of ARBs and the clinical consequences of ARB use.

Comparable efficacy and lower cost of PBSC mobilization with intermediate-dose cyclophosphamide and G-CSF compared with plerixafor and G-CSF in patients with multiple myeloma treated with novel therapies

Studies comparing the efficacy and cost of stem cell mobilization with intermediate-dose CY (ID-CY) and G-CSF against plerixafor and G-CSF, specifically in multiple myeloma (MM) patients treated in the novel therapy era, are not available. Eighty-eight consecutive patients undergoing mobilization with ID-CY (3–4 g/m2) and G-CSF (n=55) were compared with patients receiving plerixafor and G-CSF (n=33). Compared with plerixafor, ID-CY use was associated with higher median peak peripheral blood CD34+ cell count (68 vs 160 cells/μL, P<0.001), and CD34+ cell yield on day 1 of collection (6.9 × 106 vs 11.7 × 106 cells/kg, P<0.001). Total CD34+ cell yield was significantly higher in the ID-CY patients (median collection 16.6 × 106 vs 11.6 × 106 cells/kg; P<0.001). ID-CY use was associated with significantly more frequent episodes of febrile neutropenia (16.3% vs 0%; P=0.02), intravenous antibiotic use (16.3% vs 3%; P=0.03) and hospitalizations (P=0.02). The average total cost of mobilization in the plerixafor group was significantly higher compared with the ID-CY group (

Brentuximab vedotin: An anti-CD30 antibody–drug conjugate

28 980 vs

Plerixafor Salvage Is Safe and Effective in Hard-to-Mobilize Patients Undergoing Chemotherapy and Filgrastim-Based Peripheral Blood Progenitor Cell Mobilization

22 504.8; P=0.001). Our data indicate robust stem cell mobilization in MM patients treated with novel agents, with G-CSF and either ID-CY or plerixafor. When compared with plerixafor, ID-CY-containing mobilization was associated with significantly lower average total mobilization costs.

Acute Myelogenous Leukemia Patients Are at Low Risk for Invasive Fungal Infections after High-Dose Cytarabine Consolidations and Thus Do Not Require Prophylaxis

PURPOSE The pharmacology, pharmacokinetics, clinical efficacy, and safety and tolerability of brentuximab vedotin are reviewed. SUMMARY Brentuximab vedotin is a potent antibody-drug conjugate composed of the monoclonal antibody cAC10, which targets the CD30 antigen on Hodgkin lymphoma and systemic anaplastic large-cell lymphoma (sALCL) cells; a highly stable valine-citrulline linker; and a potent chemotherapeutic agent monomethyl auristatin E, which inhibits microtubule polymerization. Brentuximab is indicated for patients with relapsed Hodgkin lymphoma after autologous stem-cell transplantation (ASCT), for patients who are not candidates for ASCT who have not responded to at least two multiagent chemotherapy regimens, and for patients with ALCL who have not responded to at least one multiagent chemotherapy regimen. In a Phase II, single-group, multicenter study, brentuximab produced an overall response rate of 75% in relapsed or refractory Hodgkin lymphoma. In another Phase II study, brentuximab demonstrated clinical benefit in sALCL, with 86% of patients achieving a response and 57% of patients achieving complete remission. Adverse events most commonly reported included nausea, fatigue, diarrhea, neutropenia, and peripheral sensory neuropathy. A Phase III study is currently ongoing in patients at high risk for residual Hodgkin lymphoma after ASCT. CONCLUSION Brentuximab vedotin, a novel antibody-drug conjugate combining a cytotoxic agent with a selective monoclonal antibody, is a therapeutic option for patients with relapsed or refractory Hodgkin lymphoma and sALCL. Phase I and II studies have shown brentuximab to have a manageable toxicity profile.

Investigational drugs targeting FLT3 for leukemia

The combination of filgrastim (G-CSF) and plerixafor is currently approved for mobilizing peripheral blood progenitor cells in patients with non-Hodgkin lymphoma and multiple myeloma undergoing autologous peripheral blood hematopoietic cell transplantation. However, chemotherapy and G-CSF-based mobilization remains a widely used strategy for peripheral blood progenitor cell collection. In this paper we describe our experience from two North American transplant centers in a series of patients who received salvage plerixafor while failing chemotherapy and G-CSF mobilization. Patients received a median of two doses of plerixafor salvage upon failure to mobilize adequate number of peripheral blood progenitor cells at neutrophil recovery. The use of plerixafor was associated with a 2.4-fold increase in peripheral blood CD34+ cell count and 3.9-fold increase in total CD34+ cell yield. All patients were able to collect ≥2 × 106 CD34+ cells/kg with this approach. These results were more pronounced in patients with a higher CD34+ cell count at the time of the first plerixafor dose. Interestingly, peripheral blood white blood cell count was not shown to correlate with a response to plerixafor. Our results provide safety and efficacy data for the use of plerixafor in patients who are destined to fail chemomobilization.

Fatal Aspergillus fumigatus and Candida glabrata infections with posaconazole prophylaxis after stem cell transplantation

We evaluated the frequency of invasive fungal infections (IFI), the frequency of empirical antifungal use (EAFU), and the efficacy of fluconazole prophylaxis on IFI and EAFU after high-dose cytarabine (HiDAC) consolidations. Twenty-seven acute myelogenous leukemia patients in their first complete remission received 76 cycles of HiDAC (median cycle: n = 3). Fluconazole prophylaxis was administered following 44 cycles (fluconazole group) and not given in 32 cycles (control group). IFI (2 episodes) + EAFU (11 episodes) was observed in 13 of 76 cycles (17%); there was no difference between the fluconazole group and the control group (p = 0.469). Neutropenia duration was <13 days in 89% of the 76 cycles and was similar in the fluconazole and control groups (p = 0.845). Neutropenic fever was observed in 34 of the 76 cycles (45%) and was similar in the fluconazole group and the control group (p = 0.43). Although HiDAC cycle 1 was associated with a shorter neutropenia duration, there was no association between HiDAC cycle numbers and neutropenic fever or IFI + EAFU. HiDAC consolidations resulted in a high rate of neutropenic fever, the lack of an appreciable benefit from EAFU, and rare IFI. Most likely because of the low incidence of IFI, use of fluconazole or another antifungal is not warranted in this setting.