Jakafi Gives New Hope in Myelofibrosis

This issue of the Heme-O-Gram reviews clinical trials of oral Jakafi (ruxolitinib), the first FDA-approved medication indicated for treatment of intermediate and high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Myelofibrosis Myelofibrosis, a myeloproliferative malignancy, can be a primary disease or can develop from polycythemia vera or essential thrombocythemia.Pathogenic features of myelofibrosis include marrow fibrosis, progressive anemia, thrombocytosis or thrombocytopenia, leukocytosis or leucopenia, and splenomegaly. Patients with myelofibrosis commonly experience debilitating symptoms, such as weakness, fatigue, weight loss, cachexia, bone pain, night sweats, and pruritis. Although allogenic stem cell transplantation may be curative, few patients are candidates. Other treatments are not disease-modifying and are palliative in nature. Survival of myelofibrosis patients ranges from 2 to 11 years. Molecular Dysregulation in Myelofibrosis Dysregulation of Janus kinase (JAK), signal tranducer and activator of transcription (STAT) pathways and pro-inflammatory cytokines and growth factors that signal through JAK 1 and 2 play important roles in the pathogenesis of myelofibrosis.A JAK 2 mutation occurs in half of patients with primary myelofibrosis. About one-third of patients with myelofibrosis, however, do not have JAK-STAT-related mutations.3 Jakafi selectively inhibits JAK 1 and 2 and selectively blocks cell proliferation. Placebo-Controlled Trial of Jakafi In a double-blind, multi-center Phase 3 trial (COMFORT-I), patients with intermediate and high-risk myelofibrosis were randomized to receive either twice-daily Jakafi or placebo. Treatment resulted in reduction in size of spleen, decrease in debilitating disease-related symptoms, and improvement in overall survival. During the early part of the treatment period, patients in the Jakafi-treated group experienced more frequent anemia and thrombocytopenia. Trial of Jakafi vs Best Available Therapy In a multi-center Phase 3 trial (COMFORT-II), 219 patients with intermediate or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocytopenia myelofibrosis were randomized to receive either continuous oral Jakafi or the best available therapy. Jakafi treatment caused significant, rapid and durable reduction in splenomegaly; and other disease-related symptoms and rapidly and durably improved patients’ quality of life. In both arms of the trial, common hematological adverse events were thrombocytopenia and anemia. These were managed with reduction in dose of study drug, interruption of therapy, or transfusion. Jakafi as an Addition to the Armamentarium of Palliative Therapeutics As palliative treatment for myelofibrosis, Jakafi therapy results in a partial response in splenomegaly and reduces constitutional symptoms. An estimated 30% of patients with myelofibrosis have symptoms that are sensitive to Jakafi therapy. However, patients in the Phase 3 trials did not experience histopathologic, cytogenetic, or molecular remission of their disease. Thus, the effects of Jakafi appear to be primarily anti-cytokine in nature, rather than as a disease-modifying therapeutic. Nevertheless, oncologists view Jakafi as an important addition to choices for palliation of myelofibrosis. Jakafi should be considered as an option for myelofibrosis patients who are not candidates for potentially curative allogeneic stem cell transplantation or clinical trials of investigative drugs. For more discussion, please visit the following URLs and links: 1 www.nejm.org/doi/full/10.1056/NEJMoa1110556 2 www.nejm.org/doi/full/10.1056/NEJMoa1110557 3 www.nejm.org/doi/full/10.1056/NEJMe1115119

Does Anti-coagulation Improve Results in Cancer?

Should heparin be offered to patients with cancer who have no standard indication for anticoagulation therapy? Patients with advanced cancer, especially patients undergoing chemotherapy, commonly experience venous thromboembolism (VTE), such as deep venous thrombosis (DVT) and pulmonary embolism (PE). Consequences of venous thromboembolism include higher morbidity, hospitalization, interruption of chemotherapy, initiation of anticoagulant therapy or insertion of a vena cava filter, decreased quality of life, increased medical costs, and increased mortality.1,2 The current issue of Heme-O-Gram reviews a recent NEJM report and editorial on the potential improvement in outcomes that may be brought about by use of low molecular weight heparin (LMWH). Semuloparin Reduces Venous Thromboembolism in Cancer Patients In the SAVE-ONCO study, a multi-center double-blinded trial of 3,212 adult patients with locally advanced or metastatic cancer of various representative types who were undergoing chemotherapy patients were randomized to receive daily subcutaneous injections of either 20 mg of semuloparin, a semisynthetic, ultra-LMWH, or placebo for a median duration of 3.5 months. The treatment arm had significantly lowered incidence of venous thromboembolism (including DVT and fatal and non-fatal PE) without significantly increased major bleeding. However, the anticoagulant did not lower the mortality rate, as the rate of death in the semuloparin and placebo group was 43.4% and 44.5%, respectively.1 Pooled Analysis of Clinical Studies of Anticoagulation for Cancer Patients In the accompanying NEJM editorial on the SAVE-ONCO study, Aki and Schunemann analysed data pooled from the SAVE-ONCO study, their prior Cochrane systematic review of studies with LMWH, and another clinical trial. Using this pooled data approach of several studies they concluded that a year of treatment with LMWH in 1,000 patients with advanced cancer would result in no significant rise in major bleeding, 20 fewer thromboembolic events (and a decrease in related hospitalizations), and approximately 30 fewer deaths. The reduction in mortality was something that the SAVE-ONCO study was not strongly powered enough to demonstrate. Intriguing Mechanisms of Action of Heparins Heparins theoretically may have anti-tumor effects (including inhibiting cell to cell interactions, activity of extracellular matrix enzymes, and angiogenesis), in addition to direct anticoagulant effects.2 Antithrombotic drugs may counteract the prothrombotic effects of chemotherapy.1 Future Directions for Anticoagulant Use in Cancer Patients At the present time, guidelines recommend that cancer patients who have been hospitalized for medical illness or have undergone surgery for cancer should receive prophylaxis with anticoagulants. Given the results of the clinical studies of LMWH, stratification of risk for VTE among cancer patients, including ambulatory patients receiving chemotherapy, may be helpful.1 Ongoing and future trials may reveal whether patients with particular types and stages of solid tumors will obtain improved tumor response, quality-of-life benefits, and survival extension from adjuvant anticoagulant therapy.2 For more discussion, please visit the following URLs and links: 1 http://www.nejm.org/doi/full/10.1056/NEJMoa1108898 2 http://www.nejm.org/doi/full/10.1056/NEJMe1113672 E Thanks to everyone who has sent me feedback. Feel free to email me, or post your own comments. Stanford University

The end of watchful waiting?

Early-stage, localized (clinical stage T1 or T2) prostate cancer has been managed with “watchful waiting”, radiation therapy, or surgery plus or minus adjuvant hormonal therapy. The end of watchful waiting may soon be at hand.

Each of the above treatment modalities has potential adverse consequences. For example, surgical removal of the prostate gland can result in erectile dysfunction and urinary incontinence Accordingly, men newly diagnosed with early-stage prostate cancer and their physicians have faced difficult treatment decisions and have wondered if the outcome justified the treatment, given the slow growing nature of prostate cancer in many cases, particularly in septuagenarians and octogenarians with the disease.

But a recently published study in the New England Journal of Medicine (http://www.nejm.org/doi/full/10.1056/NEJMoa1011967) shows that radical prostatectomy in men under 65 with early-stage prostate cancer is significantly more effective than watchful waiting. The Scandinavian Prostate Cancer Group Study (SPCG-4) in Sweden, Finland, and Iceland compared outcomes of 695 patients <75 years of age with newly-diagnosed early-stage prostate cancer randomized to treatment by either watchful waiting (n = 348) or radical prostatectomy (n = 347).

Cumulative incidence of death from prostate cancer at 15 years was 14.6% for patients treated with radical prostatectomy and 20.7% for patients managed by watchful waiting.

The study also demonstrated that adjuvant local or systemic treatment of patients with extracapsular growth of prostate cancer may result in improved outcomes.

Importantly, radical prostatectomy provided significantly longer overall survival, longer prostate cancer-specific survival, and lower risk of distant metastases in men who were <65 years of age at the time of diagnosis. At 15 years after radical prostatectomy, men who were enrolled at <65 years of age with prostate cancer experienced an approximate 50% reduction in the endpoints of overall mortality, prostate cancer death, and distant metastases.

Following radical prostatectomy, men <65 with low-risk prostate cancer experienced a reduction in death by any cause, a reduction in prostate cancer death, and a decrease in distant metastases. The findings on men initially diagnosed with low-risk prostate cancer at all ages in the study suggest that some of these tumors, if not surgically removed, may progress.

In contrast, men at least 65 years of age who were diagnosed with any risk level of early-stage prostate cancer and treated with radical prostatectomy demonstrated no significant benefits in overall survival, prostate-specific survival, or reduction in distant metastases. The lack of clarity in effects of treatments in the older patients, however, may be due to lack of statistical power in the study and/or competing causes of death.

Based on the long-term data from SPCG-4, watchful waiting is no longer an option for men under 65 with early-stage prostate cancer. An aggressive approach involving surgery is recommended for these younger men. In older men with early stage prostate cancer, however, the watch-and-wait approach still can be considered as an option, at least until relative benefits of treatment modalities for the older population of patients are clarified.

Why Aren't We Doing More Breast Cancer Prevention?

Chemoprevention of breast cancer is an underutilized strategy for prevention of this very common and deadly disease. Newly published data proves that this is a developing clinical strategy and deserves the attention of any one who is involved in the health care of women.

While the ever present clamor for better breast cancer treatment continues in various forms, one of the most powerful tools against it-"chemoprevention"--continues to be ignored by the medical community. There is news now of another chemopreventive drug that should not be dismissed.

Chemoprevention is nothing more than the use of drugs to prevent an unwanted outcome-cancer-- much like using blood pressure medicine or cholesterol lowering drugs to prevent stoke and heart disease.

Tamoxifen and raloxifene (Evista) have been clearly proven as chemoprevention agents for women who are at increased risk of having breast cancer, risk factors being defined as any one of the following: age over 60, breast cell atypia, ductal carcinoma in situ (DCIS) or elevated risk score on the Gail model of breast cancer risk assessment which takes factors such as menstrual history and family history into consideration.

Despite proven efficacy with 50 percent and 38 percent reduction by tamoxifen and raloxifene respectively, prevention of breast cancer with such drugs has been an underutilized strategy. It is estimated that while over 15% of women are eligible for chemoprevention, only 0.2 % of women use chemopreventive medication. Reasons cited for such underutilization include concerns about toxicity and discomfort of primary care physicians in using drugs that have been thought of as oncologic treatments.

Tamoxifen is associated with an increased risk of venous thromboembolism, hot flashes and endometrial hyperplasia and neoplasia. Raloxifene has been associated with blood clots and stroke as well.

Excellent news now on another option is that the aromatase inhibitor, exemestane (Aromasyn) has demonstrated impressive efficacy and safety for preventing breast cancer in postmenopausal women at elevated risk In a recent international randomized double-blind study of 4,560 postmenopausal women, participants at moderate to high risk of breast cancer who received exemestane daily for up to 5 years experienced a 65% reduction in yearly incidence of invasive breast cancer at 3 years of follow-up, as compared with participants receiving placebo (www.nejm.org/doi/full/10.1056/NEJMoa1103507). These results are the biggest decline in risk of breast cancer observed in trials of any chemopreventive medication (www.cancer.gov/ncicancerbulletin/061411/page4).

Figure 2. Aromasin (exemestane)

Exemestane (Aromasyn) molecule

Moreover, exemestane significantly reduced risk of ductal carcinoma in situ (DCIS), a precursor lesion.

Additionally, exemestane has a more favorable side effect profile than does tamoxifen. When compared with placebo, exemestane did not result in a higher risk of treatment-related death, other types of cancer, cardiovascular events, or clinical skeletal fractures. Side effects of exemestane include arthritis and menopausal symptoms (such as hot flashes, arthralgia, fatigue, sweating, and insomnia).

Currently, three aromatase inhibitors, Aromasin (exemestane), Femara (letrozole), and Arimidex (anastrozole), are FDA-approved for treatment of certain types of breast cancer. At the present time, these aromatase inhibitors are not approved for primary prevention of breast cancer in post-menopausal women. Due to the efficacy and safety of exemestane, however, clinical practice eventually is likely to change to include use of exemestane for primary prevention in post-menopausal women.Other trials in progress are exploring effects of anastrozole in women at high risk of breast cancer and the combination of letrozole and tamoxifen in DCIS (www.cancer.gov/ncicancerbulletin/061411/page4).

Based on all the new information, personalized counseling of women is important in the use and choice of a chemopreventive agent and/or other strategy to lower the risk of breast cancer, reduce potential toxicity, and improve quality of life.

Excitement In Prostate and Pancreatic Cancer

Abiraterone for Advanced Prostate Caner

Castration has for long been a standard approach to treatment of men with advanced prostrate cancer. Orchiectomy and androgen deprivation with agents such as the luteinizing hormone-releasing hormone agonist drugs (e.g. Lupron) and anti-androgens (e.g Casodex) have predictable acitivity to block the effects of testosterone and/or to reduce the amount of testosterone synthesis. Inevitably, however, men with metastatic castration-resistant prostate cancer (CPRC), eventually have disease progression despite the very low levels of testosterone that such treatments induce.

A possible reason for this progression is that prostate cancer cells in these patients may have higher numbers of testosterone receptors and, therefore, are stimulated to multiply even in the presence of low testosterone in the body.

Until now, the options for treatment of CPRC patients have included second line hormonal interventions (which have not been shown to improve survival), docetaxel (Taxotere) chemotherapy, Provenge (sipuleucel-T) immunotherapy and Jevtana (cabazitaxel--a chemotherapy drug approved in 2010).

Based on a four month median survival benefit observed in a recently published pivotal clinical trial (http://www.nejm.org/doi/full/10.1056/NEJMoa1014618) , the FDA in late April approved the combination of abiraterone (Zytiga) and prednisone for men with metastatic CPRC who are no longer responding to docetaxel chemotherapy .

Abiraterone is an inhibitor of cytochrome P450 17A1 (CYP17A1), an enzyme that is involved in the conversion of cholesterol to testosterone and synthesis of other hormones, and which appears to be overexpressed in prostate cancer cells.

In the multicenter clinical trial 1195 patients were randomized to either the combination of once-daily abiraterone plus prednisone, or the combination of placebo plus prednisone. Median overall survival (OS) was 14.8 months in the abiraterone group, versus 10. 9 months in the control group. The increase in median OS in abiraterone-treated patients was statistically significant. Abiraterone was shown to be a safe drug, and relatively few serious adverse events were observed in the abiraterone arm of the trial. Since abiraterone is an oral drug, this provides a significant advantage as well.

Patients who were treated previously with the antifungal, ketoconazole, were excluded from this trial, so it is possible that such patients may experience lower responses than ketoconazole-naïve patients.

For men with metastatic CPRC who failed docetaxel treatment, Zytiga (abiraterone acetate) represents an exciting and safe therapeutic option that results in improved survival. The possibility that abiraterone could assume a front line status is being tested in an on going Phase III trial in men with metastatic CRPC who have not yet received docetaxel treatment.

Copyright 2011 A. Richard Adrouny, M.D., F.A.C.P.

Improved Survival in Pancreatic Cancer

Pancreatic cancer affects many people (it is the fourth leading cause of cancer death in the United States) and unfortunately advanced pancreatic cancer generally has a terrible prognosis. The quest for treatment regimens providing survival benefit and/or improved quality of life (QOL) is ever present. Until recently, gemcitabine (Gemzar) alone or in combination with other drugs has been considered a front line approach.

Recently the French investigator Conroy and colleagues published the results of a randomized, multicenter Phase 2-3 clinical trial comparing treatment with either the 4-drug regimen, FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) or single agent gemicitabine in 342 patients with metastatic pancreatic cancer and good performance status (http://www.nejm.org/doi/full/10.1056/NEJMoa1011923) .

Median overall survival for FOLFIRINOX-treated patients was improved by nearly 5 months to 11.1 months versus 6.8 months for gemcitabine-treated patients. The one year survival for the FOLFIRINOX patients was nearly 50% as compared to only 20% in the gemcitabine group. Moreover, FOLFIRINOX therapy resulted in statistically significant improvements in progression-free survival and objective response rates. Therefore, FOLFIRINOX-treated patients exhibited notable survival advantages, as compared with gemcitabine-treated patients.

The FOLFIRINOX-treated group, however, experienced significantly more adverse events. In most categories of toxicity, both hematologic and non-hematologic, the FOLFIRINOX patients fared less well than the gemcitabine-treated group. Nevertheless, at 6 months of treatment, patients in the FOLFIRINOX group had a decline in quality of life that was only half that of the gemcitabine group (31% vs 66%).

Thus for patients with metastatic pancreatic cancer who have good performance status FOLFIRINOX represents a first-line, chemotherapeutic option that may provide extended survival and improved QOL.

A "less is more" approach to breast cancer surgery; Shedding light on vitamin D & CLL prognosis

A "less is more" approach to breast cancer surgery

Over the past several decades, there has been a welcome trend towards less extreme surgery for women with breast cancer. The trend has continued with recently published data about axillary node dissection.

Historically, the rationale for complete axillary lymph node (ALN) dissection was detection and removal of metastases in the ALNs, a result that has important prognostic and treatment implications. But full axillary lymph node dissection (ALND) following sentinel lymph node (SLN) sampling appears to be headed toward becoming a practice of the past.-- and avoidance of ALND should result in fewer surgical complications (e.g., lymphedema, seroma, infection, and pain), increased preservation of shoulder mobility (http://journals.lww.com/oncology-times/Fulltext/2011/03100/My_Take_on_ACOSOG_Z0011_Axillary_Dissection_vs_No.5.aspx) and improved cosmetic appearance, and better self-image of patients.

In a recently published report of the ACOSOG Z011 Phase 3 clinical trial of patients with limited SLN metastatic breast cancer conducted from May 1999 to December 2004 at 115 sites in the U.S., Guiliano and colleagues demonstrated that ALND after SLN dissection (SLND) is unnecessary for good local control and excellent survival outcomes

(http://jama.ama-assn.org/content/305/6/569.full).

Almost 900 patients with early-stage invasive breast cancer who were enrolled in the trial from May 1999 to December 2004 were randomized to undergo lumpectomy, ALND (excision of ≥10 nodes), and tangential whole-breast radiation therapy (TWBRT); or lumpectomy, SLND, and TWBRT. Use of adjuvant systemic therapy (endocrine therapy and/or chemotherapy) was at the discretion of the treating medical oncologist. Approximately 96% of the ALND-treated patients and 97% of the SLND-treated patients received adjuvant systemic therapy. Median follow-up was 6.3 years.

Few recurrences occurred in the axillary nodes of patients in either group. No differences were seen in the low incidence of local and regional recurrences in the patient groups. Furthermore, patients in both groups experienced similar rates of overall survival (OS) and disease-free survival (DFS). Five-year OS was 91.8% and 92.5% in the ALND and SLND groups, respectively. Five-year DFS was 82.2% and 83.9% in patients who received ALND versus SLND.

Thus, for patients who have good prognostic indicators for breast cancers that are treated with a combination of lumpectomy, radiation therapy, and systemic therapy, good clinical outcomes may be obtained without surgical excision of involved axillary nodes. This important finding confirms the efficacy of breast-conserving surgery with adjuvant therapy, representing excellent news for women with breast cancer. Each year, thousands of women newly diagnosed with early-stage breast cancer may benefit from the high survival rates and improved quality of life provided by multi-modality therapy involving conservative surgery.

Copyright 2011 A. Richard Adrouny, M.D., F.A.C.P.

Shedding light on vitamin D & CLL prognosis

Correcting inadequate levels of vitamin D makes sense in treatment of osteoporosis, but what about cancer?

A recent article on vitamin D insufficiency and inferior prognosis of chronic lymphocytic leukemia (CLL) by Shanafelt and colleagues (http://bloodjournal.hematologylibrary.org/content/117/5/1492)is the first evidence that vitamin D deficiency is an independent risk factor in CLL and may represent the first publication that demonstrates such an association in any hematological malignancy.

Approximately 30.5% (119/390) of newly diagnosed CLL patients and almost 40% (61/153) of previously untreated CLL patients in the study were deficient in vitamin D. Following a median of 3 and 9.9 years of follow-up, respectively, the vitamin D-deficient patients in both the newly diagnosed CLL group and the CLL validation group experienced shorter time-to-treatment (TTT) and overall survival (OS).

In this provocative study, vitamin D insufficiency was associated with poorer prognosis for TTT and OS, even in early-stage CLL patients managed by a watch-and-wait approach.Based on analysis of data from all patients, adjusting for age, gender, Rai stage, status of various markers, and presence of cytogenetic abnormalities, vitamin D insufficiency was an independent predictor of TTT. Thus, vitamin D levels in serum may represent an important prognostic marker for CLL.

Because CLL currently is incurable, it would be tempting to hope, as Pepper and Fegan speculate, that normalization of vitamin D might be beneficial for CLL patients(http://bloodjournal.hematologylibrary.org/content/117/5/1439.full),and/or that vitamin D supplementation might have a chemopreventative effect on CLL incidence. Unfortunately, being cautiously optimistic may be too sunny a view at present since Shanafelt and colleagues did not study the therapeutic effects of vitamin D supplementation in CLL patients.

What about the role of vitamin D in preventing or improving outcomes in other types of cancer? Multiple, relevant mechanisms of action of vitamin D in preclinical studies on cancer abound (http://bloodjournal.hematologylibrary.org/content/117/5/1439.full).

According to a recent meta-analysis by an Institute of Medicine (IOM) panel, however, the inconsistent research on vitamin D insufficiency and incidence and mortality of many types of solid tumors and non-Hodgkin's lymphoma - as well as that of cardiovascular disease, diabetes, and autoimmune diseases - does not prove a cause-effect relationship (www.nejm.org/doi/full/10.1056/NeJMp1102022). Most past research has been based on lab, ecologic, and observational studies of vitamin D levels in serum, whereas no completed large-scale randomized clinical trials of vitamin D intake have included cancer as the pre-specified, primary endpoint. Another reason for the difficulty in interpreting prior clinical studies on cancer epidemiology is that vitamin D deficiency has been associated with known cancer risk factors, such as obesity, insufficient physical activity, dark skin pigmentation, and dietary habits.

Five to six years from now, data from ongoing clinical trials of moderate to high doses of vitamin D for chemoprevention of cancer will be available(Chustecka, 3/31/11, www.medscape.com; subscription required). Also, many clinical studies of vitamin D and its derivatives as therapeutics for a variety of cancers are in progress. In a best-case scenario, perhaps eventually we will be able to add prevention or treatment of some type of cancer as another rationale for vitamin D supplementation in certain patients. On the other hand, without compelling evidence of beneficial effect in other diseases, osteoporosis and related bone conditions remain the bona fide reasons for normalizing vitamin D.

Copyright 2011 A. Richard Adrouny, M.D., F.A.C.P.

Non-hormonal, non-surgical therapy for menorrhagia; new drug for renal carcinoma; new thrombophilia

FDA approves tranexamic acid for menorrhagia

The U.S. FDA approved tranexamic acid tablets (Lysteda, Xanodyne Pharmaceuticals), the first non hormonal product cleared to treat menorrhagia.

Tranexamic acid was first approved by the FDA in 1986 as an injection, under the brand name Cyklokapron, and is used to reduce or prevent bleeding during and following tooth extraction in patients with hemophilia.
 It is a synthetic lysine derivative that exerts its antifibrinolytic effect by reversibly blocking lysine binding sites on plasminogen and thus preventing fibrin degradation.

The most common adverse reactions reported in clinical trials included headache, sinus and nasal symptoms, back pain, abdominal pain, muscle and joint pain, muscle cramps, anemia, and fatigue. There was a statistically significant reduction in menstrual blood loss in women who received Lysteda, compared with those taking placebo. Use of Lysteda while taking hormonal contraceptives may increase the risk of blood clots, stroke, or heart attack.

FDA approval of pazopanib for advanced renal cell cancer

Another drug, pazopanib (Votrient, GSK) has been added to the growing menu of options for treatment of advanced renal cell cancer, a disease for which only a few years ago we had few treatment choices. The approval was based on a phase III trial of 435 patients with advanced renal cell cancer who were randomized to either the drug or placebo. The response rate was 30% in the treated group, compared to 3% in the placebo group. The treated group did not show progression of their disease for a median duration of 11 months, compared to 2.8 months for the placebo group.

Pazopanib is an oral drug, and works by inhibiting angiogenesis, which is believed to play an essential role in the growth and spread of malignant tumors.

This is the sixth renal carcinoma drug approved since 2005. (The others are sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), everolimus (Afinitor) and bevacizumab (Avastin). All of these drugs are considered “targeted therapies” in contrast to conventional chemotherapy drugs. They each have a specific molecular target. None of these drugs have yet been studied in direct comparison with each other. Other approved drugs for advanced renal cell carcinoma include interleukin 2 and interferon. Trials of combinations of these agents, as well comparison studies of drugs head to head, are likely to be reported in the future.

New form of genetic thrombophilia reported

You can now add Factor IX Padua to your list of thrombophilic disorders. This gain of function genetic variant of Factor IX was identified in a patient with venous thromboembolism by physicians in--you guessed it--Padua, Italy. The subject patient was found to have nearly 800% of normal activity of factor IX. The genetic defect that he carried is a point mutation in the factor IX gene (G31134T transversion) that caused a substitution of leucine for arginine at position 338. Other family members were found to have varying degrees of abnormality, not nearly as great as the proband.

Since Factor IX activity elevation is in the differential of thrombophilic disorders, it seems possible that this specific abnormality could be added in the future to the laboratory evaluation of thrombophilia. Studies will have to be carried out to estimate the frequency of this abnormality in the general population. http://content.nejm.org/cgi/content/full/361/17/1671