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

Tamoxifen pharmacogenetics; GI cancers aren't sexy; vascular complications of splenectomy

Tamoxifen pharmacogenetics affects clinical outcomes

There is a growing list of drugs whose metabolism (and clinical effects) have been shown to be influenced by genetic mutations. (See my posts of March 1 and March 15, 2009: http://adrounysheme-o-gram.blogspot.com/2009_03_01_archive.html).

Besides important drugs like warfarin and clopidgorel (Plavix), tamoxifen effect has also been shown to be influenced by mutations of a metabolizing enzyme, in this case, cytochrome P450 2D6 (CYP2D6) enzyme.

The Oct 7 2009 issue of JAMA (http://jama.ama-assn.org/cgi/content/full/302/13/1429) features a German-American collaboration on clinical outcomes with tamoxifen stratified according to metabolizer type. Tamoxifen has been a foundation of breast cancer treatment for the last 30 years. Its growth inhibitory effect on breast cancer is mediated by metabolites 4-hydroxytamoxifen and endoxifen. The formation of these active metabolites is catalyzed by CP2D6. One hundred variants of CYP2D6 have been identified with four distinct phenotypes of metabolism: extensive (normal activity); intermediate (reduced activity), poor (no activity) and ultrarapid (high activity). A gene-dose effect has been demonstrated.

The study included almost fourteen hundred women from Germany and the U.S. with stages I, II and III who were given tamoxifen according to standard practices and who underwent pharmacogenetic analysis. Endpoints included standard oncologic parameters, including disease free survival and overall survival. Median follow-up was over six years.

The best results were seen in the extensive (normal activity) metabolizers. The overall recurrence rate was nearly double in the poor metabolizer group (24% vs 12.5%) and the death rate was significantly higher in the poor metabolizer group (22.8% vs. 16.7%)

This study is not the first to suggest an association between CYP2D6 mutations and clinical outcomes. However, it is the first with enough statistical power to actually prove the relationship.

The use of CYP2D6 testing is not yet a clinical standard. It may well become one. I have observed that at least one insurance company has been routinely demanding testing of patients who are prescribed tamoxifen.

An Interesting Comment

“For lack of a better word, GI cancers aren’t particularly sexy, certainly not from a political standpoint, nor is it easy to attract the blandishments of corporate largesse when the victims of these diseases comprise such a nebulous consumer base. Thus…it really falls on our shoulders to inspire and lead our patients and advocacy groups in an effort to increase funding, improve clinical trial participation, or incite a bit of a ‘riot’, if that’s what it takes to shatter insouciance and ensure that GI cancers get the attention they deserve…I strongly believe we can change the outlooks of patients with these terrible diseases…Our patients deserve better than run-of-the-mill interventions and should be demanding optimum treatment.”—John L. Marshall, M.D., Chief, Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University. Quoted in Gastrointestinal Cancer Research Volume 3 Issue 4.

Splenectomy induces a hypercoagulable state

Over 20,000 splenectomies are performed annually in the U.S. Besides a higher incidence of overwhelming sepsis, there are concerns about other potential long term complications of splenectomy. A recent article in Blood http://bloodjournal.hematologylibrary.org/cgi/content/full/114/14/2861 reviews the possibility that splenectomy induces a higher incidence of vascular complications.

Spleen contains white pulp and red pulp. White pulp is largely lymphoid tissue that processes antigens and produces antibodies. Red pulp consists of the sinusoidal cords of Billroth, which filter the blood by removing aged and damaged cells and by “polishing” red cells that have developed surface imperfections. The red pulp also contains a reservoir of platelets and granulocytes.

A number of potential vascular complications have been identified in post-splenectomy patients. These include arterial events such as stoke, M.I., carotid disease and peripheral arterial disease.

Venous events, both local and systemic, have been identified. The incidence of portal vein thrombosis after splenectomy ranges from 5 to 37%. Fatal pulmonary embolism was 5 times higher in persons with previous splenectomy than in matched controls in one autopsy study.

Pulmonary arterial hypertension is another potential vascular complication.

The authors speculate that the higher incidence of vascular events has multifactorial causes, resulting from hypercoagulability, platelet activation, disturbance and activation of the endothelium and altered lipid profiles. Absence of the filtration function of the spleen may permit particulates and cell debris to activate vascular endothelium. Splenectomy increases platelet counts, cholesterol, C-reactive protein, white count and hemoglobin concentration, all of which are associated with increased risks of arterial and venous thrombosis.

The authors conclude that further study of this is warranted, particularly with respect to issues such as whether short or long term thromboprophylaxis should be offered patients who have had splenectomy.

An alternative to warfarin for A. fib? ; The Great Influenza

Dabigatran for atrial fibrillation

The NEJM recently published a lead article (http://content.nejm.org/cgi/content/full/361/12/1139) which compared dabigatran to warfarin in patients with atrial fibrillation. Dabigatran belongs to a new class of oral anticoagulants known as DTI’s (direct thrombin inhibitors) which are in development. (See my Heme-O-Gram of Dec. 14 ’08 http://adrounysheme-o-gram.blogspot.com/2009/03/new-oral-anticoagulant-drugs-report.html )

While the effectiveness of warfarin for stroke prevention in atrial fibrillation is in little doubt, warfarin is probably underutilized because of a number of reasons primarily relating to inconvenience and risk of bleeding. Drugs like dabigatran offer several advantages over warfarin: fixed dose, shorter half-life, no need for monitoring, wide therapeutic index, oral administration, general convenience. The question is whether it meets non-inferiority with a tried and true agent like warfarin. Previously, dabigatran was shown to be as effective and safe as enoxaparin (Lovenox) in reducing VTE after orthopedic surgery.

The RE-LY (Randomized Evaluation of Long-Term Anticoagulation) trial, which accrued and randomized over 18,000 patients, the standard of non-inferiority for atrial fibrillation appears to have been met with respect to the primary outcome, either stroke or systemic embolism. The study was funded by Boehringer Ingelheim, the manufacturer of dabigatran. Two doses of dabigatran were studied: 110 mg and 150 mg each given b.i.d. The 18,000 patients were evenly matched across the three study groups.

The lowest rate of stroke/systemic embolism occurred in the group receiving dabigatran 150 mg bid (1.11. % per year compared to 1.69% for warfarin and 1.53% for dabigatran 110 mg bid.) Both dabigatran doses were non-inferior to warfarin but only the higher dose was superior. Bleeding rate was highest in the warfarin group (3.36% per year) and lowest in the dabigatran 110 mg bid group (2.71% per year). In the dabigatran 150 mg bid group, the rate was 3.11% per year.

The only significantly increased adverse effect in the dabigatran treated patients was dyspepsia. There were higher rates of myocardial infarction in the dabigatran groups, but not statistically significant. The authors hypothesize that warfarin may have a more protective effect in coronary disease than dabigatran.

There were also higher rates of discontinuation in both dabigatran groups, apparently because of GI symptoms and other unspecified serous adverse events. The authors do not go into any detail to explain the latter.

The quality of warfarin administration was good, as evidenced by a 64% rate of therapeutic INR in the warfarin treated group.

In conclusion: dabigatran appears to be non inferior to warfarin both in terms of efficacy and complications for prophylaxis of stroke and systemic embolism in patients with atrial fibrillation. As part of a new class of oral anticoagulants, dabigatran appears to be headed towards approval for use in a variety of settings. Keep yours eye open for this new drug.

Hemorrhagic complications of influenza

“Then there was the blood, blood pouring from the body. To see blood trickle, and in some cases spurt, from someone’s nose, mouth, even from the ears or around the eyes, had to terrify.

“One of the most striking of the complications was hemorrhage from mucous membranes, especially from the nose, stomach, and intestine. Bleeding from the ears and petechial hemorrhages in the skin also occurred.

“One German investigator recorded ‘hemorrhages occurring in different parts of the interior of the eye’ with great frequency. An American pathologist noted: ‘Fifty cases of subconjunctival hemorrhage were counted. Twelve had a true hemoptysis, bright red blood with no admixture of mucus…Three cases had intestinal hemorrhage…’

These frightening descriptions of “the flu” come from the book The Great Influenza by John M. Barry, an outstanding treatise on the history of the 1918 flu pandemic and the history of American medicine and its response to the medical emergency posed by the pandemic. With current concerns about H1N1 virus, it made me wonder if we might expect similar dramatic clinical manifestations.

But surprisingly (and happily), clinical descriptions of the current H1N1 flu outbreak, which conceivably has the potential to reach pandemic levels, are surprisingly tame with respect to hematologic complications. Both mild leukocytosis and leucopenia have been seen according to reports. A substantial incidence of pulmonary embolism was reported in five of 10 ICU patients hospitalized with H1N1 and ARDS in Michigan and “hypercoagulable state” was reported to be evident in two additional patients. Otherwise, there seems little to report. I will keep watch on this.

Reversal of anti-coagulation--when should you get excited?

Reversal of anti-coagulation--when should you get excited?

Friends and Colleagues:

When I attended the 2008 ASH (American Society of Hematology) annual meeting in San Francisco in

December, I attended a very informative and practical talk by Dr. Mark Crowther of McMaster University on the

topic of anticoagulation reversal.

When you have a patient who is having major bleeding and an INR > 15, it seems pretty clear that immediate

action in the form of factor replacement is needed. What is possibly less well appreciated is that the non-bleeding

patient with prolonged INR of almost any degree rarely if ever should be given infusions of plasma or factor

concentrates.

Dr. Crowther began his talk with fundamental principles: don't lose your cool, stop warfarin, assess the situation, administer antidotes if needed, allow time for anticoagulant drugs to clear.

If the INR is between 5 and 9 and there is no bleeding, the American College of Chest Physicians (ACCP)

recommends holding warfarin and monitoring. If the situation is urgent (i.e. there is high risk of bleeding or

surgery is needed) one can consider giving Vitamin K 1 mg orally (subcutaneous administration is not advised

due to erratic absorption). Dr. Crowther cited four clinical trials that demonstrated that while vitamin K

administration was superior to simple withdrawal of warfarin in reducing the INR, it was not superior in reducing

the incidence of bleeding. Therefore, if you can wait it out, the moral of the story is that simply stopping warfarin and monitoring the INR is an appropriate management strategy, even with an INR as high as 9.

If the INR is higher than 9 and there is insignificant bleeding, higher doses of oral vitamin K (2.5 to 5 mg) and INRmonitoring are suggested.

What if there is major bleeding? The ACCP recommends stopping warfarin, giving IV vitamin K (10 mg, slowly),

giving plasma and/or factor concentrates and repeating IV vitamin K every 12 hours. Dr. Crowther recommended the use of factor concentrates in addition to FFP, since the latter rarely completely corrects the factor deficit,

unless given in unacceptably large volumes. Factor concentrates can provide dramatically fast correction of the INR, in comparison to FFP.

Consensus: Menorrhagia work-up should include consideration of a bleeding disorder

The July 2009 issue of the American Journal of Obstetrics and Gynecology will report the results of a September 2007 consensus conference, with participation by experts in ob-gyn and hematology on the diagnosis and management of reproductive tract bleeding in women with bleeding disorders http://www.ajog.org/article/S0002-9378(09)00410-4/fulltext. The conference was predicated on the belief that the lack of awareness of the potential of bleeding disorders to exacerbate or cause abnormal bleeding leads to underdiagnosis and suboptimal treatment of women with bleeding disorders.
The report brings to light some interesting numbers. For example, the prevalence of menorrhagia in women with von Willebrand Disease (vWD) is between 74 and 92%; conversely, the prevalence of vWD in women with menorrhagia is between 5-24% A study was cited that reported a 33% prevalence of vWD is adolescents with menorrhagia.
The fact that as many as one in every four women with menorrhagia could have a diagnosis of vWD is an impressive one, and surprising. The statistic of one in three for adolescents is even more striking.
The report points out that most women with menorrhagia do not have a bleeding disorder and that even in women with a known bleeding disorder, a gyn evaluation for other causes of bleeding is still mandatory. An underlying bleeding disorder should be considered, however, if any of the following indicators are present:
menorrhagia since menarche
family history of bleeding disorder
personal history of epistaxis lasting more than 10 minutes or necessitating packing or cautery
"notable" bruising without injury
minor wound bleeding, e.g. from trivial cuts, lasting for more than five minutes
bleeding from an oral cavity or GI tract without obvious anatomic lesion
prolonged bleeding after dental extraction
unexpected postsurgical bleeding
hemorrhage from ovarian cysts or corpus luteum, with or without Mittelschmerz
hemorrhage requiring blood transfusion
postpartum hemorrhage, especially when delayed
failure of response to conventional management of menorrhagia
Hematologic evaluation is most sensitive during menstruation, when coagulation factors are at their lowest. However, evaluation should not be delayed until menstruation. Tests can be repeated during menstruation if initial testing is at low normal. Patients should not be removed from contraceptives to permit testing although patients with mild vWD may have normal results when contraceptives are being used. A concluding comment from this article includes the following: "collaboration among obstetrician-gynecologists and hematologists ...could lead to a decrease in the diagnosis of "idiopathic" menorrhagia and allow more effective management of bleeding events." Another conclusion reached is that consideration of bleeding disorders in menorrhagia can lead to improved management of post-partum hemorrhage.

What is the optimum duration of warfarin therapy? Only your ultrasonographer knows for sure...

VTE (venous thromboembolic) disease is a potentially chronic disorder. In one study, the eight year risk of recurrent VTE was 30% in patients with unprovoked events.

The challenge physicians face is to decide who needs longer duration of therapy, and who doesn't, since there is the potential for fatal thrombotic complications in the former group, and serious bleeding complications in the latter. Optimum duration of warfarin therapy has been debated for years, and several different approaches have been taken to make a decision about treatment duration.

In patients whose VTE is provoked by an identifiable and reversible factor (e.g., pregnancy, BCP's, estrogen replacement, recent surgery, recent fracture, long distance air travel, prolonged hospitalization) the duration of therapy can be limited to three to six months. (Recent guidelines published in Chest (http://www.chestjournal.org/content/133/6_suppl) include the option of only three months of therapy for provoked P.E.)

The problem arises in those whose VTE is seemingly unprovoked, or in whom the provocative factor may be a little iffy. These are the patients who deserve a work-up for underlying hypercoagulable state, and who may also benefit from prolonged warfarin therapy, perhaps even lifelong in duration.

In 2003, the NEJM published two articles only several months apart, looking at the results of using prolonged low intensity warfarin therapy (target INR 1.5-2.0), which came to opposing conclusions. In one, the results of the PREVENT trial (http://content.nejm.org/cgi/content/abstract/348/15/1425), a benefit was found in giving prolonged low intensity warfarin even when compared to full intensity anticoagulation. The other trial, named ELATE (http://content.nejm.org/cgi/content/abstract/349/7/631), did not show such a benefit. Thus, the practice of prolonged low intensity warfarin therapy has not really caught on much, although it's something that I do in my practice.

On the other hand, measurement of D-dimer following completion of a specified period of anti-vitamin K therapy, was found to be helpful in predicting whether a person would have recurrence of VTE. The PROLONG study was published in the NEJM in 2006 (http://cme.nejm.org/cgi/content/abstract/nejm;355/17/1780), and this showed that patients with an abnormal D-dimer level one month after the discontinuation of warfarin had a significant incidence of recurrent VTE which can be reduced by the continuation of anticoagulation. Interestingly, the group of patients who had a normal D-dimer had a higher hazard rate of recurrence, compared to the high D-dimer group that received anticoagulation, suggesting that there are yet other factors that may predict long term outcome. Good reviews of the science and clinical application of D-dimer can be found in the journal Blood (http://bloodjournal.hematologylibrary.org/cgi/content/short/113/13/2878) and in the Annals of Internal Medicine (http://www.annals.org/cgi/content/abstract/149/7/481)

Another study (http://jama.ama-assn.org/cgi/content/abstract/296/4/397) looked at thrombin generation time after discontinuation of anticoagulation as a means of determining risk; the patients with lower incidence of recurrent VTE had lower mean peak thrombin generation times. This study, although interesting, has low practical value at the present time.

Most recently, the Annals of Internal Medicine (http://www.annals.org/cgi/content/short/150/9/577) published a provocative article suggesting that the presence of recanalization of veins on follow-up ultrasonography (UTS) is a predictor of long term outcomes for patients with DVT. In this study, 538 patients who had received an initial three months of anticoagulation were randomly assigned to receive either a fixed duration of anticoagulation therapy or flexible duration of therapy whose length was determined by UTS findings at pre-determined intervals. In both the fixed group and the flexible group, the patients were further subdivided into those who had unprovoked DVT or provoked DVT. In the fixed group, the patients with unprovoked DVT received an additional three months of anticoagulation (for a total of six months.) Both groups of patients were subjected to serial UTS up to 21 months if vein recanalization was not observed.

But in the flexible group, the decision to continue anticoagulation was based solely upon serial UTS performed at 3, 9, 15 and 21 months. If the UTS showed resolution of thrombus (defined as vein recanalization), then anticoagulation was discontinued. The mean duration of anticoagulation in the flexible group with provoked DVT was 3.7 months and in unprovoked DVT was 5 months.

There were 78 episodes of recurrent VTE in the 538 patients. The incidence was 17.2% treated in the fixed duration arm, and 11.9% in the flexible duration arm. The cumulative incidence of recurrent VTE was less in the flexible group than in the fixed group. Bleeding complications were higher in the flexible group than in the fixed, but not significantly so.

These results suggested that "assessment of residual thrombosis by ultrasonography improves the identification of patients who are at highest risk for recurrence, and it allowed decisions on anticoagulation that led to a substantial reduction in recurrent events." An interesting note is that prolonging anticoagulation seemed to accelerate vein recanalization, because there was a significantly smaller proportion of patients with persistent vein obstruction in the fixed group than in the flexible group after the last UTS exam in both groups. The authors further conclude that residual thrombosis is a marker of hypercoagulability and that it may predict late cardiovascular death.

This study is a very interesting one (with some limitations) and suggests that follow-up UTS may be a useful adjunct to other clinical evaluations that are used in making the decision whether to continue anticoagulation in patients with DVT. (Note that this study was not about patients with P.E.) In my opinion, this study does suggest that residual thrombi on follow-up UTS should be taken seriously and should prompt continued anticoagulation, and so it does confirm to me the value of my usual practice of obtaining a follow-up UTS after a prescribed course of anticoagulation.

What I was not able to tell from this paper was whether the predictive value of a follow-up ultrasound could be determined early on, or if multiple serial UTS was absolutely required. Clearly this has important economic implications, as well as patient compliance and utilization questions.

"Never Events" and VTE

“Never Events” and VTE

If you have not heard of “Never Events”, I encourage all of you to read Rich Fox’s timely commentary in the Healthcare Journal of Northern California on this regulatory phenomenon enacted by CMS (US Centers for Medicare and Medicaid Services) (http://www.hcjnc.com/index.php/editorial-mainmenu-31/45-editorial/219-never-events.html)

Effective October 1, 2008, Medicare stopped reimbursing hospitals for the added costs of treating complications arising during hospitalization that in its view should never happen. As Rich points out, this doesn’t mean that Medicare won’t pay for any of the hospitalization, just the part of the DRG that was added on by the never event.

Venous thromboembolism (deep vein thrombosis and pulmonary embolism) occurring after total knee replacement and hip replacement is one of the ten never events.

A recent commentary in JAMA (JAMA vol. 301, p.1063-1065)explores this item in some detail. The authors point out that currently many hospitalized patients fail to receive adequate VTE prophylaxis. Accordingly, financial incentives should in theory improve clinical outcomes.

However, the assumption seems to be that all venous thromboembolism can be prevented. As the authors state, “VTE prophylaxis is not perfect. The most effective currently available prophylactic regimens do not prevent all thrombotic events following TKA or THA.” Nor is VTE prophylaxis always complication proof. There is a significant risk of bleeding complicating VTE prophylaxis with anticoagulants. The authors point out that this risk is probably underestimated in most clinical trials of anticoagulant prophylaxis because the selection criteria tend to favor younger and healthier individuals.

Hospitals that have a disproportionate population of Medicare patients may suffer because of higher rates of both VTE and bleeding. This may result in disincentives to treat higher risk patients.

The authors also suggest that the rule creates disincentives to perform TKR or THR and orthopedists may shift their practices to other types of procedures, or there may be an outright reduction in the number of medical students choosing orthopedics as their specialty. Somehow the logic of this escapes me, since the financial penalties fall only to the hospitals. But I guess there is always the possibility that eventually doctors themselves may be penalized.

They also suggest that this may actually disincentivize doctors to pursue the diagnosis of VTE, if they fear that this will result in a financial penalty to the hospital. I am not sure I would agree with that either.

Their last point, which is not arguable, is that focusing on TKR and THR actually only accounts for less than 10% of the patients who develop VTE in hospitals. This fails to address all of the other areas where improvements can be made in VTE prophylaxis.

The authors conclude with their strongest point: CMS should link penalties only to cases of post-operative VTE where adequate VTE prophylaxis was not given. The bureaucracy based assumption that all cases of VTE are preventable is simply ridiculous.

Pharmacogenetics Strikes Again, This Time with Warfarin

Dosing of warfarin is one of the most challenging problems in clinical practice today. This drug has a narrow therapeutic index, and achieving therapeutic objectives can be very cumbersome for both patient and physician. Various algorithms have been devised to solve this problem.It is well established that variations in two genes, one in the cytochrome P450 family (CYP2C9) and the other in the vitamin K epoxide reductase complex (VKORC1) play important roles in the variable dose requirements that different patients have for warfarin.A study recently published in the NEJM (http://content.nejm.org/cgi/content/abstract/360/8/753) demonstrated that a pharmacogenetic algorithm incorporating clinical information and information on these two genetic mutations performed better than an algorithm based solely on clinical factors or a fixed dose of 5 mg per day in predicting the correct dose requirement for warfarin.

I think the most interesting outcome of this retrospective study is the demonstration that significant percentages of patients had requirements well below and above the fixed dose of 5 mg per day. 33.9% of patients required 21 mg or less per week (<3>7 mg or more per day). It was in these outlier groups that the pharmacogenetic algorithm performed better than the clinical algorithm.

Does this mean that everyone should be tested for CYP2C9 or VKORC1?

No--not yet. As pointed out in the accompanying editorial (http://content.nejm.org/cgi/content/full/360/8/811), warfarin dosing is and always will be empiric, since "the pharmacodynamic end point is the entire basis of warfarin dosage." As yet, there is no randomized prospective trial demonstrating that pharmacogenetic testing and algorithmic dosing provides a clinical benefit. This study however could be the precursor to such a study.

From a clinical standpoint, it is important to remember that when a patient requires what seems like an unusually high or low dose of warfarin to obtain a therapeutic INR, it is most likely related to polymorphisms of either one of these genes, and one should not necessarily doubt the veracity of the INR test result.

The New England Journal of Medicine recently published two articles and an editorial on the impact of cytochrome P-450 polymorphisms and response to clopidogrel (Plavix) in its January 22, 2009 issue.

Clopidogrel is an inhibitor of the platelet P2Y12 receptor that requires activation by specific cytochrome P-450 (CYP) enzymes. Specifically, reduced responsiveness has been associated with specific alleles of the CYP2C19 and CYP3A4 genes.

In one study, from France, it was found that patients carrying any two CYP2C19 loss of function alleles had higher event rates after acute MI when treated with clopidogrel than those who did not carry such alleles. In the other study, from Boston, carriers of at least one CYP2C19 loss of function allele who were treated with clopidogrel had higher risk of stent thrombosis, death from MI and stroke as compared to non-carriers.

(Prasugrel, another P2Y12 inhibitor not yet on the U.S. market, appears to be unaffected by CYP2C19 variability. Recently, the FDA Cardiovascular and Renal Drugs Advisory Committee voted to approve prasugrel for the treatment of patients with acute coronary syndromes (ACS) managed with percutaneous coronary intervention (PCI). Prasugrel is accompanied by an increased risk of serious bleeding events compared to clopidogrel.)

As the accompanying NEJM editorial noted, it is not yet clear whether routine genetic testing should be performed when considering drug treatment with clopidogrel.

Here is a link to the editorial: http://content.nejm.org/cgi/content/full/360/4/411

Here are the links to the articles:

http://content.nejm.org/cgi/content/abstract/360/4/363?ijkey=d835d191649f69a7c7880c766fdafb735f12b812&keytype2=tf_ipsecsha

http://content.nejm.org/cgi/content/abstract/360/4/354?ijkey=bf3b57074b8ce114bdc5184612a9bef892a772cf&keytype2=tf_ipsecsha

One more caveat: The CYP2C19 enzyme referred to above is not the same as the CYP2C9 enzyme involved in the metabolism of warfarin, single nucleotide polymorphisms of which have been implicated in the variability of dosing that some people require when being treated with warfarin.

New Drugs for ITP

The world of platelets and ITP has gone through some changes lately with the approval of two new drugs for ITP and the presentation of data on the use of established drug rituximab (Rituxan) for ITP at the recent American Society of Hematology (ASH) annual meeting earlier this month.

Approval of Nplate (romiplostim)(Amgen) came in August of this year, while approval of Promacta (eltrombopag) (GSK) came in in November. The main practical difference between these drugs is that Nplate is administered subcutaneously on a weekly schedule, while Promacta is given orally on a daily basis..

Both Nplate and Promacta have indications for patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Both drugs are thrombopoietin (TPO) receptor agonists that stimulate bone marrow megakaryocytes to produce platelets.

Areas of concern about these drugs have to do with increased reticulin formation and fibrosis in the bone marrow, thrombogenic potential from too high an increase in platelets, and possible malignant transformation to leukemia, especially in myelodysplastic disorders (MDS). Also, discontinuation of drug may cause rebound thrombocytopenia.

Although Nplate was the first to receive approval, it is my guess that Promacta will be more widely used given its oral availability. However, cost of both of these new drugs could limit their use. And, given that ITP is relatively uncommon, it is my guess that these drugs may try to find broader use in other situations, such as chemotherapy induced thrombocytopenias, MDS and chronic thrombocytopenia from hypersplenism due to chronic liver disease. The market potential in these situations is much larger.

In other news, the combination of Rituxan plus dexamethasone was reported by Italian investigators to be significantly better in inducing initial and sustained responses in patients with ITP than dexamethasone alone, in a plenary session abstract presented at the ASH annual meeting. It was concluded that the option of treatment with Rituxan plus dexamethasone could be offered as an option before splenectomy, particularly in patients who are at high risk of complications from surgery or who are reluctant to undergo splenectomy.

New oral anticoagulant drugs: report from ASH 2008

I had the privilege of attending last week's annual meeting of the American Society of Hematology, held in San Francisco. It was one of the most interesting meetings I have ever attended. I paid particularly close attention to the abstracts and educational symposia in the field of thrombosis and anticoagulant therapies.

What interested me the most is the emergence of new oral anticoagulants. These drugs fall into the category of direct thrombin inhibitors (DTIs) and factor Xa inhibitors.

The ideal anticoagulant drug would be one with a wide therapeutic index, oral administration, once a day administration, easy reversibility and availability of an effective antidote, short half life, lack of need for laboratory monitoring and reasonable cost.

While unfractionated heparin, low molecular weight heparins and warfarin in their own respects fulfill some of the above characteristics, none of them are by any means ideal and they all fall far short of fulfilling all of the above criteria.

The drugs to be on the watch for in my opinion are going to be rivaroxaban (Xarelto-Bayer), apixaban (Pfizer and BMS) and dabigatran (Pradaxa-Boehringer Ingelheim) which come much closer to being the "ideal" drug. The latter drug is a DTI that has been shown to be as effective and safe as enoxaparin (Lovenox) in reducing VTE after orthopedic surgery, while the first two are factor Xa inhibitors. Rivaroxaban has received approval in Canada and the EU for prevention of VTE in patients undergoing elective total hip or total knee replacement surgery. Apixaban failed to meet pre-specified criteria of non-inferiority in a study comparing it to enoxaparin in post-op patients but was numerically very similar in efficacy and statistically superior in terms of bleeding complications.

Also to watch for are potential antidote drugs, in particular one that is in development from Portola Pharmaceuticals (S. San Franciso), which is directed against the Xa inhibitors.