Platelet Transfusions Detrimental in TTP and HIT

SUMMARY: Patients with Thrombotic Thrombocytopenic Purpura (TTP), Heparin Induced Thrombocytopenia (HIT) and Immune Thrombocytopenic Purpura (ITP) often receive prophylactic platelet transfusions even though there are no data to support this practice. These transfusions are often given preemptively to reduce the risk for spontaneous bleeding in patients who are thrombocytopenic. Thrombocytopenia refers to a platelet count below the lower limit of the normal range used by the laboratory performing the count. In the United States, a little over 2 million platelet units are transfused annually. The known risks associated with platelet transfusion include febrile and allergic reactions, Transfusion Related Acute Lung Injury and infections. The authors in this study utilized a Nationwide Inpatient Sample of patients over a 5 year period from 2007-2011and evaluated the risks associated with platelet transfusions. They identified 10,624 hospitalizations with TTP and platelet transfusions were reported in 10.1%, 6,332 hospitalizations with HIT and 7.1% received platelet transfusions and 79,980 admissions with ITP and 25.8% received platelet transfusions. The Odds Ratio (OR) was calculated after adjusting for age, gender, clinical severity and acuity. (An Odds Ratio is a measure of association between an exposure and an outcome. The OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure). The researchers noted some alarming findings. Platelet transfusions in TTP were associated with higher odds of arterial thrombosis (OR=5.8), Acute Myocardial Infarction (OR=2.0) and mortality (OR=2.0). Platelet transfusions in HIT were associated with higher odds of arterial thrombosis (OR=3.4) and mortality (OR=5.2). Platelet transfusions in TTP or HIT however, was not associated with venous thrombosis. There were no increased risks among patients with ITP, who received platelet transfusions. The authors concluded that until future trials provide additional information, platelet transfusions should be considered a relative contraindication in patients with TTP and HIT and should only be used in situations where severe or potentially life threatening bleeding is refractory to other therapies. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Goel R, Ness PM, Takemoto CM, et al. Blood. 2015;125:1470-1476.

Clinical Cancer Advances 2015 Annual Report on Progress Against Cancer From the American Society of Clinical Oncology (PART II)

SUMMARY: Cancer mortality rates in the United States have declined 20% from their peak of 215 per 100,000 in 1991 to 172 per 100,000 in 2010. Part II  of this Annual Report on Progress Against Cancer explores, ADVANCES IN TREATMENT, ADVANCES IN TUMOR BIOLOGY AND ADVANCES IN PATIENT CARE. Clinical study details for several of these studies can be accessed at www.oncoprescribe.com

ADVANCES IN TREATMENT

COMBINATION THERAPY

Chemotherapy and Radiotherapy significantly improves Survival for Patients with Low-Grade Glioma – Radiotherapy has been the standard first-line treatment for patients with low-grade glioma. In a study involving 251 patients with gliomas which included grade 2 Astrocytoma, Oligoastrocytoma, or Oligodendroglioma, the addition of chemotherapy (PCV regimen – (Procarbazine, Lomustine, and Vincristine) to radiation extended median survival by 5.5 years (13.3 vs 7.8 years, P=0.03; HR=0.59) and also resulted in a longer median Progression Free survival (10.4 vs 4 years, P=0.002; HR=0.50), when compared with radiotherapy alone.

First-Line Chemotherapy Added to Hormone Therapy Improves Survival for Men With Advanced Prostate Cancer – Androgen Deprivation Therapy (ADT) has been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for hormone sensitive prostate cancer. Chemotherapy is usually considered for patients who progress on hormone therapy. In a pivotal phase III study which included 790 men with metastatic, hormone-sensitive prostate cancer, the addition of TAXOTERE® (Docetaxel) chemotherapy to ADT improved median Overall Survival by 10 months from 42.3 months in the ADT alone group to 52.7 months in the ADT plus TAXOTERE® group (HR=0.63; P<0.0006). The median time to clinical progression was 19.8 months in the ADT alone group vs 32.7 months in the ADT plus TAXOTERE® group (P < 0.0001).

TARGETED THERAPY

Overcoming Resistance to EGFR Targeted Agents in Lung Cancer– TARCEVA® (Erlotinib) and GILOTRIF® (Afatinib) are recommended as first-line treatments for patients harboring Epidermal Growth Factor Receptor (EGFR) gene mutations, which are detected in 15% of Caucasian and 40% of Asian patients with NSCLC. An additional EGFR mutation (T790M) is responsible for resistance to EGFR-targeted therapy and may be detected in about 50% of those harboring EGFR mutations in Non Small Cell Lung Cancer (NSCLC). AZD9291 and CO-1686 are two new agents which have demonstrated a 50-60% response rate in patients with T790M mutation.

New second-line treatment options for ALK-positive NSCLC – XALKORI® (Crizotinib) significantly improves PFS and Response Rates in patients with ALK-positive NSCLC. Approximately one third of these patients are resistant to XALKORI® and this has been attributed to acquired mutation within the ALK tyrosine kinase domain, amplification of the ALK fusion gene, subtherapeutic inhibition of ALK tyrosine kinase or activation of other pathways that can cause abnormal cell proliferation. ZYKADIA® (Ceritinib) resulted in an overall Response Rate (RR) of 58% and median PFS of 7 months in this patient population, with responses seen in untreated CNS lesions as well.

FDA Approves First Treatment for Chemotherapy-Resistant, Advanced Stomach Cancer –  CYRAMZA® (Ramucirumab) an angiogenesis inhibitor was approved for the treatment of advanced stomach cancer or gastroesophageal junction adenocarcinoma that progressed during or after chemotherapy. The approval was based on a phase III trial involving 355 patients in which patients treated with CYRAMZA® (Ramucirumab) had longer survival (5.2 vs 3.8 months, HR = 0.78, P=0.047), when compared to placebo.

Lenvatinib: A New Option for a Difficult-to-Treat Thyroid Cancer –  LENVIMA® (Lenvatinib) a Tyrosine Kinase Inhibitor, was approved for the treatment of patients with locally recurrent or metastatic, progressive, RadioActive Iodine (RAI)-refractory Differentiated Thyroid Cancer (DTC). In a phase III study involving 392 patients with advanced RAI-refractory Differentiated Thyroid Cancer (DTC), the median Progression Free Survival was 18.3 months in the LENVIMA® group and 3.6 months in the placebo group (HR= 0.21; P<0.001). The objective response rate with LENVIMA® was 64.8% versus 1.5% with placebo (P<0.001). Another targeted drug, NEXAVAR® (Sorafenib), was approved for the same patient population in 2013.

IMMUNOTHERAPY

Both antibody and cell-based immunotherapy approaches have taken center stage in cancer immunotherapy. Check point inhibitors such as anti CTLA-4. Anti PD-1 and anti PDL1 antibodies unleash the immune system allowing the T cells to attack the malignant cells.

Adjuvant Immunotherapy For Early Stage Melanoma – YERVOY® (Ipilimumab), an anti CTLA-4 antibody decreased the relative risk of recurrence by 25% (HR=0.75; P=0.0013), when compared with placebo, in patients with high risk, completely resected, stage III melanoma

Immunotherapy in Lung Cancer – OPDIVO® (Nivolumab), a PD-1 targeted monoclonal antibody improved overall survival by 41% (HR=0.59; P=0.00025) when compared to TAXOTERE® (Docetaxel) in a randomized phase III trial in patients with metastatic squamous NSCLC, who had experienced disease progression during or after one prior platinum-based chemotherapy regimen. KEYTRUDA® (Pembrolizumab) another PD-1 antibody demonstrated superior responses in patients with lung cancer when the tumors were PD-L1 positive versus PD-L1 negative (23% vs 9%) suggesting that PD-L1 may be a predictor of response to PD-1 and PD-L1 therapies.

Tumor Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy – In this type of immunotherapy, T cells are collected from the patient’s own blood and are genetically engineered to produce special receptors on their surface called chimeric antigen receptors (CAR’s). These cytotoxic T cells with these chimeric antigen receptors on their surface are now able to recognize a specific antigen on tumor cells. These engineered CAR T-cells (CTL019) which are grown in vitro, are then infused into the patient and they in turn proliferate in the patient’s body, recognize and kill cancer cells expressing that specific antigen. In a small study of patients with relapsed or refractory ALL, treatment with autologous Chimeric Antigen Receptor (CAR) T-cells (CTL019 T-cells) resulted in a 90% remission rate with sustained remissions for up to 2 years and overall survival of 78%.

ADVANCES IN TUMOR BIOLOGY

Genomic Profile Based Therapy – In a recent landmark study, analysis of molecular data from approximately 3,500 patients with 12 different forms of cancer, lead to the identification of 11 major molecular subtypes. It was noted that most malignancies that originated from the same tissue or organ had similar genomic profiles. Treatment in the foreseeable future may be based on genomic profile rather than site of origin of the malignancy.

Blood Test Predicts Resistance to Prostate Cancer Therapy – In patients with metastatic CRPC, the presence of Androgen Receptor Variant AR-V7 rather than a normal androgen receptor, in the circulating tumor cells (CTCs) before, during, and after treatment with either XTANDI® (Enzalutamide) or ZYTIGA® (Abiraterone), conferred resistance to these agents. The Androgen Receptor Variant AR-V7 was detected in roughly 40% of patients treated with XTANDI® and 20% of those treated with ZYTIGA®.

Gut Bacteria and Response to Therapy – Two early studies have demonstrated that Intestinal bacteria may be beneficial in priming and mobilizing immune cells to attack tumors. Further, certain chemotherapeutic agents such as CYTOXAN® (Cyclophosphamide) and ELOXATIN® (Oxaliplatin) were less effective when intestinal bacteria were eradicated with antibiotics.

ADVANCES IN PATIENT CARE

Early Initiation of Palliative Care Improves Patient Well Being – In a study of close to 500 patients with advanced cancer early palliative care improved, quality of life at the end of life, spiritual well-being, symptom severity, and satisfaction with care at 4 months after diagnosis.

Pregnancy After Breast Cancer Treatment – Premature Ovarian Failure (POF) is a common unintended consequence of chemotherapy in premenopausal women. Besides loss of fertility, which can influence treatment decisions in young women, ovarian failure can lead to menopausal symptoms, sexual dysfunction and loss of bone density. Two studies reported a promising new way of preserve fertility. In the POEMS (Prevention of Early Menopause Study) phase III trial, the addition of ZOLADEX® (Goserelin) to chemotherapy decreased the POF to 8% compared to 22% with chemotherapy alone (P=0.04). More women in the ZOLADEX® group achieved at least one pregnancy (21%) compared to 11% in the chemotherapy alone group (P=0.03). In a different study, similar findings were noted with the addition of another hormonal agent, TRELSTAR® (Triptorelin) to chemotherapy.

Masters GA, Krilov L, Bailey HH , et al. Published online before print January 20, 2015, doi: 10.1200/JCO.2014.59.9746

Cancers associated with BRCA1 and BRCA2 mutations other than Breast and Ovarian

SUMMARY:Approximately 5-10% of all Breast and Ovarian cancers are caused by inherited genetic factors and are typically the result from inherited mutations in either the BRCA1 or BRCA2 gene. BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively. They control cell growth by repairing DNA damage and thus prevent tumor development. Mutations in these genes predispose an individual to develop malignant tumors. The presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing Breast and Ovarian cancer, as high as 85% and 40% respectively. While the association of BRCA1 and BRCA2 mutations with Breast and Ovarian cancer risks is well-established, the potential association of these mutations with other cancers has remained unclear. This study was conducted to evaluate the incidence of cancers other than Breast and Ovarian cancer, in known BRCA1 and BRCA2 mutation carriers. The study population included 1072 patients who had received genetic counseling at the UT MD Anderson Cancer Center between 1997 and 2013 and had a confirmed BRCA1 (N=613) or BRCA2 (N=459) mutation. The authors then compared the cancer incidence of the study population with the United States Cancer Statistics. The expected and observed numbers of cancer cases were calculated at 5 year intervals to take into consideration different age-related incidence rates. Standardized Incidence Ratios (SIRs) for each cancer type was then calculated for the entire sample and for BRCA1 mutation carriers and BRCA2 mutation carriers separately. {Standardized Incidence Ratio (SIR) is used to determine if the occurrence of cancer in a relatively small population is high or low. A SIR of 1 would indicate no increase or decrease, SIR of 1.5 indicates an excess of 50%, SIR of 2 indicates an excess of 100%}. Among the study population, 1177 cancers comprising 30 different cancer types were identified. There was no significant increase in cancers other than Breast and Ovarian cancer in individuals with BRCA1 mutation, but there was a trend of increasing incidence of Melanoma in BRCA1 mutation carriers, compared to general population. Individuals with BRCA2 mutation however had significantly higher incidence of Pancreatic cancer in both men and women (SIR= 21.7; P < 0.001), Prostate cancer in men (SIR= 4.9; P = 0.002) and a trend of increasing incidence of Cervical cancer, compared to general population. The authors concluded that their findings support the NCCN practice guidelines for this patient population which includes screening for male Breast cancer, Prostate cancer and Melanoma, acknowledging that specific screening guidelines for Pancreatic cancer do not exist. Mersch J, Jackson MA, Park M, et al. Cancer 2015; 121:269-275

Clinical Cancer Advances 2015 Annual Report on Progress Against Cancer From the American Society of Clinical Oncology (PART I)

SUMMARY: Cancer mortality rates in the United States have declined 20% from their peak of 215 per 100,000 in 1991 to 172 per 100,000 in 2010. With more than half a million Americans diagnosed with cancer each year, recent advances in cancer treatment and research has lead to improved survival and better quality of life, with 14.5 million cancer survivors alive in the US today. This Annual Report on Progress Against Cancer explored the clinical advances of the prior year (2014), that made the greatest impact on improving cancer care. This report was developed based on research published in peer-reviewed scientific and medical journals and information presented at major scientific meetings over a one year period between October 2013 to September 2014. A brief summary of this report (Part I) is presented. Part I includes, ADVANCE OF THE YEAR and ADVANCES IN PREVENTION AND SCREENING. Clinical trial details for several of these studies can be accessed at www.oncoprescribe.com

ADVANCE OF THE YEAR – TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA

Chronic Lymphocytic Leukemia (CLL) is the most common form of adult leukemia and is more common in the elderly. Four new therapies associated with fewer toxicities compared with standard therapy, were recently approved for patients with CLL.

Two Effective Treatment Options for Patients with Newly Diagnosed CLL

GAZYVA® (Obinutuzumab) is a fully humanized, third generation, type II, anti-CD20 monoclonal antibody that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. In a phase III trial involving 589 treatment naïve CLL patients, GAZYVA® in combination with LEUKERAN® (Chlorambucil) more than doubled the Progression Free Survival (PFS) from 11.1 months with LEUKERAN® alone to 26.7 months (HR=0.18, P<0.001). The combination of GAZYVA® and LEUKERAN® also prolonged Overall Survival (OS) when compared to LEUKERAN® alone (HR=0.41; P=0.002). This benefit however was not noted with the RITUXAN® plus LEUKERAN® combination. Treatment with GAZYVA® plus LEUKERAN® when compared with RITUXAN® plus LEUKERAN® resulted in a longer PFS (26.7 vs15.2 months; HR=0.39; P<0.001), higher complete response rates (20.7% vs 7.0%) and deeper molecular responses.

ARZERRA® (Ofatumumab), a second generation fully human IgG 1 monoclonal antibody, which targets a different region (different epitope) of the CD20 molecule in combination with LEUKERAN®, was compared with LEUKERAN® alone, as first line treatment in a study involving 447 CLL patients. The median PFS was 22.4 months for patients receiving ARZERRA® in combination with LEUKERAN® compared with 13.1 months for those receiving single agent LEUKERAN® (HR=0.57, P< 0.001). The Objective Response Rate was higher with the combination regimen versus single agent LEUKERAN® (82% vs 69%, P=0.001).

Two New Non-Chemotherapy Alternatives for Relapsed and Treatment-Resistant CLL

IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). IMBRUVICA® was compared to single agent ARZERRA® in a phase III trial involving 391 patients with relapsed CLL. Thirty percent (30%) of the patients had deletion of chromosome 17p. At a median follow up of 9.4 months, IMBRUVICA® significantly prolonged PFS compared to ARZERRA® (median not reached vs 8.1 months; HR 0.215, P<0.0001) with a 78.5% reduction in the risk of disease progression and also significantly improved OS (median not reached, HR 0.43, P=0.0049) when compared with ARZERRA®, with a 57% reduction in the risk of death.

In a phase III study involving 220 previously treated patients with recurrent CLL, ZYDELIG® (Idelalisib), a highly selective oral inhibitor of the enzyme PhosphoInositide 3-Kinase (PI3K) that specifically blocks the delta isoform of PI3K enzyme and its signaling pathway, was combined with RITUXAN® and compared with placebo given along with RITUXAN®. The median PFS with ZYDELIG® in combination with RITUXAN® was significantly prolonged compared with Placebo and RITUXAN® (10.7 months vs 5.5 months). An improvement in the Overall Survival (OS) was also noted in the ZYDELIG® group compared with patients in the RITUXAN® and placebo group (HR = 0.28; P = 0.018).

ADVANCES IN PREVENTION AND SCREENING

Breast Cancer Prevention

The only two drugs currently approved by the FDA to prevent breast cancer are NOLVADEX® (Tamoxifen) and EVISTA® (Raloxifene). These agents block the estrogen receptors and can be used in both pre and postmenopausal women. NOLVADEX® is however associated with thromboembolic evens as well as endometrial carcinoma. ARIMIDEX® (Anastrozole), an Aromatase Inhibitor (AI), in a randomized, double blind, placebo controlled trial, involving 3864 women at increased risk of breast cancer, reduced this risk of breast cancer by 53% compared to placebo, over a 5-year period (P<0.0001), in post-menopausal women. This benefit with ARIMIDEX® was accomplished without increase in the risk of heart attacks or fractures, compared with placebo. There was however increase in the incidence of joint and muscle pain as well as hot flushes and night sweats. Another AI, AROMASIN® (Exemestane) in a previously published study (MAP.3 trial) significantly reduced the incidence of all breast cancers by 53% and invasive breast cancers by 65%, after a median follow up of 3 years.

Screening for Lung Cancer

The United States Preventive Services Task Force (USPSTF) recommended annual screening for lung cancer with Low Dose Computed Tomography in adult individuals, between ages 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. The use of Low Dose CT (LDCT) scans for 3 years in this high risk, healthy patients, resulted in a 20% reduction in Lung cancer mortality, compared to screening with a chest X-Ray in the NCI-sponsored National Lung Screening Trial (NLST).

Masters GA, Krilov L, Bailey HH, et al. Published online before print January 20, 2015, doi: 10.1200/JCO.2014.59.9746

Platelet Transfusion A Clinical Practice Guideline from the AABB

SUMMARY: Platelets are often transfused preemptively to reduce the risk for spontaneous bleeding in patients who are thrombocytopenic following chemotherapy or hematopoietic stem cell transplantation. In the United States, a little over 2 million platelet units are transfused annually. The risks associated with platelet transfusion such as febrile and allergic reactions, Transfusion Related Acute Lung Injury and infections, have to be taken into consideration before transfusion is planned. Further, unlike other blood products, platelets must be stored at room temperature and this limits the platelet unit shelf life to only 5 days, to prevent the risk for bacterial growth during storage. This in turn is an additional burden to the hospital blood banks. The AABB (American Association of Blood Banks) commissioned and funded the development of platelet transfusion guidelines with the help of 21 experts from various specialties of medicine, after a systematic review of 17 randomized controlled trials and 53 observational studies. A platelet unit in this guideline refers to 1 apheresis platelet unit or a pool of 4-6 whole blood derived platelet concentrates, containing approximately 3- 4 x 1011 platelets. Thrombocytopenia refers to a platelet count below the lower limit of the normal range used by the laboratory performing the count. Six recommendations were made for 4 different clinical settings.

Hospitalized Adult Patients with Therapy-Induced Hypoproliferative Thrombocytopenia

Recommendation 1: The AABB recommends that platelets should be transfused prophylactically to reduce the risk for spontaneous bleeding in hospitalized adult patients with therapy-induced hypoproliferative thrombocytopenia. The AABB recommends transfusing hospitalized adult patients with a platelet count of 10 × 109 cells/L or less to reduce the risk for spontaneous bleeding. The AABB recommends transfusing up to a single apheresis unit or equivalent. Greater doses are not more effective, and lower doses equal to one half of a standard apheresis unit are equally effective.

Adult Patients Having Minor Invasive Procedures

Recommendation 2: The AABB suggests prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count less than 20 × 109 cells/L.

Recommendation 3: The AABB suggests prophylactic platelet transfusion for patients having elective diagnostic lumbar puncture with a platelet count less than 50 × 109 cells/L.

Adult Patients Having Major Elective Non-neuraxial Surgery

Recommendation 4: The AABB suggests prophylactic platelet transfusion for patients having major elective non-neuraxial surgery with a platelet count less than 50 × 109 cells/L.

Recommendation 5: The AABB recommends against routine prophylactic platelet transfusion for patients who are non-thrombocytopenic and have cardiac surgery with cardiopulmonary bypass. The AABB suggests platelet transfusion for patients having bypass who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction.

Adult Patients Receiving Antiplatelet Therapy Who Have Intracranial Hemorrhage (Traumatic or Spontaneous)

Recommendation 6: The AABB cannot recommend for or against platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous).

The authors acknowledge that the platelet transfusion threshold recommendations made by the various medical specialty societies, may be different, but the evidence based recommendations provided herein, will complement clinical judgment, as individualized decisions are made, to transfuse platelets. Kaufman RM, Djulbegovic B, Gernsheimer T, et al. Ann Intern Med. 2015;162:205-213.

The Second ASH CHOOSING WISELY® Campaign Five Hematologic Tests and Treatments to Question

SUMMARY: CHOOSING WISELY® is a quality improvement initiative led by the American Board of Internal Medicine Foundation in collaboration with leading medical societies in the United States such as the American Society of Hematology (ASH). This organization was established to improve quality of medical care, after it was noted that about 25% of the tests ordered at the time of hospital admission and 65% of the tests ordered on subsequent days were avoidable. Further, there is ample evidence to suggest that reducing unneeded investigations can decrease costs, increase patient satisfaction and quality of care. CHOOSING WISELY® has challenged medical societies to identify 5 tests, procedures or treatments, within each specialty's clinical domain, that are offered to patients, despite the lack of evidence demonstrating its benefit. The goal is to make positive changes in the actual delivery of patient care. The 2014 Task Force was comprised of 13 individuals representing a broad spectrum of hematologic expertise including malignant, benign, adult, and pediatric specialists. The five final recommendations of the 2014 ASH Choosing Wisely Campaign are summarized below. Practicing hematologists should give due consideration to these recommendations which are evidence based and cost effective.

ASH recommendation #1: In patients with a first VTE (Venous ThromboEmbolism) provoked by a major, transient VTE risk factor such as surgery, trauma, or an intravascular catheter, do not treat with an anticoagulant for more than 3 months. There is a low risk of VTE recurrence after three months in this setting and anticoagulation for VTE continued beyond three months may be associated with increased bleeding risk, particularly in the elderly and those with comorbidities. This recommendation is not applicable to patients with non-major, transient VTE risk factors such as travel-associated immobility, pregnancy or hormone use. Women who experience a first VTE during pregnancy should receive anticoagulation until at least six weeks post-partum, for a minimum total duration of three months or longer. VTEs occurring in the context of estrogen supplements are associated with a low recurrence rate following discontinuation of hormonal therapy/oral contraceptives and three months of anticoagulation may be adequate. However, the optimal duration of anticoagulation for VTEs provoked by hormones or by travel remains unclear and should be determined on a on a case-by-case basis.

ASH recommendation #2: Routine transfusion of PRBC for chronic anemia or uncomplicated pain crises in patients with sickle cell disease is not recommended as these patients who are predominantly African Americans, are at an especially higher risk for alloimmunization to minor blood group antigens, which can result in delayed-hemolytic transfusion reactions, as well as difficulty finding compatible blood when necessary. The baseline hemoglobin values range between 7 and 10g/dL in stable patients with severe sickle cell disease and these patients are often able to tolerate a 1-2g/dL decreases in their hemoglobin values following IV hydration. Further, data does not strongly support that episodic red cell transfusion reduces pain during acute vaso-occlusive crises. Moreover, iron overload from repeated transfusions can cause significant morbidity and mortality in patients with sickle cell disease.

ASH recommendation #3: Unlike in other lymphoproliferative diseases, routine surveillance CT scans are not recommended in patients with asymptomatic, early stage chronic lymphocytic leukemia (CLL). Both the Rai and Binet staging systems are based on physical exam findings and complete blood counts and prognosis can be assessed with molecular mutational analyses. CT scans are therefore not necessary and can be potentially harmful, by exposing patients to radiation and may also trigger additional workup to evaluate incidental findings (Cascade effect), that may not be of importance.

ASH recommendation #4: Do not test or treat for suspected Heparin-Induced Thrombocytopenia (HIT) in patients with a Low pretest probability of HIT. The 4Ts is a pretest scoring system for HIT and incorporates 4 components of HIT which include magnitude of thrombocytopenia, timing of thrombocytopenia with respect to heparin exposure, thrombosis or other sequelae of HIT and likelihood of other causes of thrombocytopenia. The 4Ts score is the sum of the values for each of the 4 categories. A score of 0-3 is classified as Low, 4-5 as Intermediate and 6-8 as High pretest probability for HIT. The negative predictive value of a Low 4T’s score is close to 100% in adults. Further, Enzyme ImmunoAssays (EIA) for HIT have a high false positive rate and a positive EIA HIT test results in a patient with a Low 4T’s score is much more likely to represent a false positive value than true positive. Confirmatory testing with serotonin release assays are not easily available and can be expensive. Misdiagnosing HIT can harm patients by denying them a heparin preparation in the future and the use of alternative, expensive anticoagulants such as Argatroban in these thrombocytopenic patients can be associated with a higher risk of bleeding. For these reasons, testing for HIT is only cost-effective when the pre-test probability of HIT is greater than 8%, which corresponds to an Intermediate or High 4T’s score

ASH recommendation #5: Do not treat patients with Immune Thrombocytopenic Purpura (ITP) in the absence of bleeding or a very low platelet count. ITP is often a temporary condition in children and resolves without treatment and treatment is not recommended in childhood ITP unless there is bleeding or risk factors for bleeding. ITP in adults is usually a chronic disease with remissions and exacerbations and patients with a platelet count of 30,000/microL or more and with no bleeding, can be observed without intervention. Steroids can impair glucose metabolism, increase infection risk, cause adrenal suppression and in children can cause growth impairment. Splenectomy is associated with perioperative risks and small risk of life threatening infections. Rituximab can cause Hepatitis B reactivation and TPO receptor agonists are only cost-effective in the setting of severe ITP, refractory to other treatment interventions.

Hicks LK, Bering H, Carson KR, et al. Prepublished online December 3, 2014; doi:10.1182/blood-2014-09-599399

Promise and Pitfalls of Heavy-Particle Therapy

SUMMARY: Radiation Therapy involves the use of X-Rays, gamma rays and charged particles for cancer treatment. External-beam radiation therapy is most often delivered using a linear accelerator in the form of Photon beams (either x-rays or gamma rays). Photons have no mass and are packets of energy of an electromagnetic wave. Electrons and Protons are charged particles and Electrons are considered light particles whereas Protons are considered heavy particles. Electron beams are used to irradiate skin and superficial tumors, as they are unable to penetrate deep into the tissues. The different types of external beam radiation treatments include 3-Dimensional Conformal Radiation Therapy (3D-CRT) meant to deliver radiation to very precisely shaped target areas, IMRT or Intensity Modulated Radiation Therapy which allows different areas of a tumor or nearby tissues to receive different doses of radiation, Image Guided Radiation Therapy (IGRT) which allows reduction in the planned volume of tissue to be treated as changes in a tumor size are noted during treatment, Stereotactic RadioSurgery (SRS) which can deliver one or more high doses of radiation to a small tumor, Stereotactic Body Radiation Therapy (SBRT) or CYBERKNIFE® which is similar to SRS but also takes the normal motion of the body into account while treating malignancies involving the lung and liver and Proton Beam therapy. Proton beams unlike Photons, enter the skin and travel through the tissues and deposit much of their energy at the end of their path (known as the Bragg peak) and deposit less energy along the way. This is unlike Photons which deposit energy all along the path through the tissues and the deposited dose decreases with increasing depth. As a result, with Proton beam therapy, normal tissues are exposed to less radiation compared with Photons. Despite this advantage, tissue heterogeneity such as organ motion, tumor volume changes during treatment can have a significant negative impact on target coverage for Proton beam therapy and can result in damage to the surrounding tissues and potential complications. The authors in this review discussed the clinical applications of Proton therapy in Adult and Pediatric malignancies. Pediatric patients with malignancies have greater benefit with Proton beam therapy, with a statistically significant lower risk of secondary malignancies and less damage to the developing tissues and organs, compared to Photon therapy (External Beam Radiation Therapy). This clinical benefit may be less so in adult malignancies in spite of superior dosimetry, compared to external beam radiation, as adults are less prone to secondary malignancies compared to children.

ADULT MALIGNANCIES

Prostate Cancer: Majority of the patients receiving Proton beam treatment in the United States have prostate cancer. Several randomized trials have concluded that higher radiation dose to the prostate gland leads to better tumor control. Proton beam therapy may deliver this promise, but with associated toxicities, in particular rectal bleeding. This is by virtue of the anatomy of the prostate gland which is deep in the pelvis. Outcomes and patient reported side effects were similar when men with prostate cancer were treated with similar doses of radiation using either Proton beam therapy or External beam radiation therapy. The American Society of Therapeutic Radiology and Oncology (ASTRO) has recommended that Proton beam therapy for patients with prostate cancer should be offered in the context of a clinical trial or registry, as there is not enough evidence suggesting clinical benefit in this patient population.

Breast Cancer: Proton beam therapy may be of value in select situations, such as patients with bilateral implants after mastectomy and in clinical scenarios where cardiac or pulmonary risks with Photon therapy are not acceptable. This is because of a significant reduction in the radiation doses to the heart, lung and contralateral breast with Proton therapy compared to Photon therapy.

Lung Cancer: Proton beam therapy for NSCLC (Non Small Cell Lung Cancer) is in the early stages of evaluation and has the advantage of reduced radiation to the normal lung and heart. This may be relevant in patients with inoperable early stage NSCLC with poor lung function, prior chest irradiation or in those with multifocal lung cancers requiring more than one treatment course. Proton therapy can be of significant value in patients with Stage IIIA NSCLC who in addition to chemoradiation may be candidates for pneumonectomy, thus sparing the contralateral lung from radiation related toxicities.

Head and Neck Cancers: Proton therapy may be of value in nasopharyngeal carcinoma and malignancies involving the oropharynx and paranasal sinuses. Proton therapy limits the radiation dose to the brain stem, optic structures, mandible and salivary glands, decreasing the risk of xerostomia and osteoradionecrosis of the mandible.

GI Malignancies: Proton beam therapy is the preferable treatment for hepatocellular carcinoma in patients with Child-Pugh class B and class C cirrhosis, as it is able to spare more liver tissue from radiation.

Brain Tumors: Meningiomas are ideal tumors for Proton beam therapy, with less cerebral adverse events and therefore has a positive impact on quality of life of patients. Clinical trials are underway to test this hypothesis.

PEDIATRIC TUMORS

Medulloblastoma- CranioSpinal Irradiation: There is a significant long term advantage with Proton CranioSpinal Irradiation compared to conventional or IMRT photon CSI. There is a 6-12 times lower risk of secondary malignancies due to lower radiation doses to normal tissues. This is more relevant because craniospinal axis irradiation results in the most exposure of a childs tissue to radiation.

Rhabdomyosarcoma: This is the most common soft tissue sarcoma in children arising in the head and neck region and Proton therapy can significantly reduce the mean doses to the retina, optic nerve, parotid and cochlea.

Ependymoma, Craniopharyngioma, Retinoblastoma and Glioma: Proton therapy for these tumors has been associated with lower acute and long term toxicities as well lower risk of secondary malignancies.

The authors concluded that the most benefit for Proton beam therapy is in pediatric malignancies, no significant benefit in skin cancer and marginal benefit in adult lung and prostate cancer. With ongoing advances in the delivery of Proton therapy such as Intensity Modulated Proton Therapy (IMPT) and other expensive therapeutic interventions, economics will take precedence, until and unless a clear clinical benefit is proven. Mitin T and Zietman AL. J Clin Oncol 2014;32:2855-2863

Cancer of Unknown Primary Site

SUMMARY:Carcinoma of Unknown Primary Site (CUPS) is a heterogeneous clinical pathologic syndrome for which the anatomical site of origin of the primary tumor is clinically undetectable. CUPS accounts for approximately 2% of all advanced malignances annually. The American Cancer Society estimates that about 31,430 cases of Cancer of Unknown Primary site will be diagnosed in 2014 in the United States. The pathobiology of tumors from unknown primary sites is similar to those with detectable primary tumors and therefore may respond to therapies similar to those with easily detectable primary tumors. Historically, the treatment approach for patients with CUPS included broad spectrum empiric chemotherapy. Histological evaluation of the biopsy tissue alone has been the standard practice for decades. With the availability of gene expression profiling assays and advances in ImmunoHistoChemistry staining as well as imaging technology, predicting the tissue of origin of the primary tumor and tailoring therapy accordingly, has improved overall survival in this patient population. Evaluation of a patient with CUPS starts with gathering and incorporating medical information which includes the patient’s gender, medical history, clinical findings and sites of metastases. A CT scan of the chest, abdomen and pelvis with IV and oral contrast is recommended, although PET (Positron Emission Tomography) or an MRI can be performed in those with renal insufficiency or iodine allergy. PET scan is recommended for those with cervical lymphadenopathy with squamous histology, to help determine the extent of the disease and treatment planning for radiation. PET imaging is also helpful for patients with solitary metastases before locoregional therapies are planned, as well as assessing response in patients with predominantly bone only disease. In women presenting with isolated axillary lymphadenopathy, adenocarcinoma histology, negative mammograms and ultrasound, MRI of the breasts is indicated. With the exception of those patients with CUPS who present with cervical lymphadenopathy, diagnostic procedures such as bronchoscopy, EGD and colonoscopy are not recommended in asymptomatic patients. Tumor markers in general do not have diagnostic value in patients with CUPS although they could be utilized to monitor response to treatment. However, PSA when elevated in a male with adenocarcinoma and osteoblastic metastases, is suggestive of a prostate primary. Similarly an elevated Beta HCG and AFP in a patient with undifferentiated or poorly differentiated carcinoma, is suggestive of an extragonadal germ cell tumor and an elevated AFP is also helpful in making a diagnosis of Hepatoma. Approximately 60% of the patients with CUPS have well or moderately differentiated adenocarcinoma on light microscopy, 30% have poorly differentiated carcinoma or adenocarcinoma, 5% have poorly differentiated or undifferentiated malignancy and 5% have squamous cell carcinoma. Following histological evaluation on light microscopy, the biopsy specimen is further tested using ImmunoHistoChemical stains, using peroxidase labeled antibodies against tumor specific antigens, taking advantage of the similarities in the tumor profiles of primary and metastatic malignancies. After delineating a tumor as carcinoma, lymphoma, sarcoma or melanoma, additional IHC testing can help identify tumors such as a lung primary (postive Thyroid Transcription Factor 1-TTF1and positive CytoKeratin 7- CK7), lower gastrointestinal cancers (positive CK20, positive CDX2 and negative CK7) or a breast primary (positive CK7 and positive Mammaglobin). Tissue-of-Origin molecular profiling is based on the principle that in patients with CUPS, molecular signatures of metastatic tumors are similar to their primary tumor. Tissue-of-Origin molecular profiling is performed using tools such as DNA microarray, quantitative real time polymerase chain reaction assay (rt-PCR) or assays based on messenger RNA (mRNA) or microRNA. These tests are cost-effective and 70% – 90% accurate. This study can be performed on formalin-fixed samples as well as samples from fine needle aspiration. Even though platinum based chemotherapy has been the default regimen for patients with CUPS, histological evaluation of biopsy tissue by light microscopy, IHC testing and molecular profiling assay may complement each other and help guide the Health Care Provider to select site specific therapy. The survival outcomes of CUPS patients with a Tissue-of-Origin molecularly diagnosed profile are comparable to those with similar type advanced cancer with a known primary. The authors concluded that with additional molecular insights into tumor biology and availability of newer therapeutic agents, patients with CUPS and known primary tumors may eventually be treated alike. Varadhachary, GR and Raber, MN. N Engl J Med 2014; 371:757-765

Phase 3 study of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting during repeated moderately emetogenic chemotherapy (MEC) cycles

SUMMARY: Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most common adverse effects of chemotherapy and is experienced by about 80% of patients receiving chemotherapy. The development of effective antiemetic agents has facilitated the administration of majority of the chemotherapy agents in an outpatient setting avoiding hospitalization. Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on serotonin (5-hydroxytryptamine-5HT3) and its receptors. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are located peripherally on the nerve endings of the vagus and centrally in the Chemoreceptor Trigger Zone of the area Postrema. Chemotherapeutic agents produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems. Netupitant inhibits substance P mediated responses. ALOXI® (Palonosetron) is a second generation 5-HT3 antagonist and has a 100 fold higher binding affinity to 5-HT3 receptor than other 5-HT3 receptor antagonists. AKYNZEO® (300 mg Netupitant/0.5 mg Palonosetron) is an oral, fixed combination product of Netupitant, a substance P/Neurokinin 1 (NK1) receptor antagonist, and ALOXI®, a serotonin (5- HT3) receptor antagonist. Taking advantage of the different mechanisms of action and synergy between these two agents, a randomized, double-blind, multinational study was conducted, comparing AKYNZEO® with ALOXI® in chemotherapy naive patients receiving anthracycline based chemotherapy regimens. One thousand four hundred and fifty five (N=1455) were randomized to receive either AKYNZEO® or ALOXI® and both groups received oral Dexamethasone as a part of their antiemetic regimen. The primary endpoint was complete response (CR) defined as no emesis, no rescue medication needed and no significant nausea. AKYNZEO® maintained superiority over ALOXI® for overall (0-120 hours) complete response and also maintained superiority over multiple chemotherapy cycles (P < 0.0001). The most common side effects for AKYNZEO® were headache, fatigue and constipation. The authors concluded that AKYNZEO®, by targeting dual antiemetic pathways, significantly improved chemotherapy induced nausea and vomiting compared to ALOXI® alone and this benefit was maintained over multiple cycles of moderately emetogenic chemotherapy. AKYNZEO® capsule can be administered as a single dose, one hour prior to the start of chemotherapy. Aapro MS, Karthaus M, Schwartzberg LS, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 9502)</s

Electronic Cigarettes A Position Statement of the Forum of International Respiratory Societies

SUMMARY: According to the American Cancer Society, tobacco use is responsible for nearly 1 in 5 deaths in the United States and accounts for at least 30% of all cancer deaths. Smokeless tobacco products are a major source of cancer causing nitrosamines and increase the risk of developing cancer of the oropharynx, esophagus, and pancreas. Cigarette smoke contains more than 7,000 chemicals, many of which are toxic and some linked to cancer. E-cigarettes were first developed in China and were introduced to the U.S. market in 2007. When a smoker inhales through the mouth piece of an E-cigarette, the air flow triggers a sensor that switches on a small lithium battery powered heater, which in turn vaporizes liquid nicotine along with PolyEthylene Glycol (PEG) present in a small cartridge. The PEG vapor looks like smoke. The potent liquid form of nicotine extracted from tobacco is tinctured with fragrant flavors such as chocolate, cherry and bubble gum, coloring substances, as well other chemicals and these e-liquids are powerful neurotoxins. With the rapid growth of the E-cigarette industry and the evidence of potential dangers and risk to public health, particularly children, experts from the world's leading lung organizations were compelled to release a position statement on electronic cigarettes, specifically focusing on their potential adverse effects on human health and calling on government organizations to ban or restrict the use of E-cigarettes, until their impact on health is better understood. With epidemiological data demonstrating that nicotine use is a gateway to the use of cocaine and marijuana and subsequent lifelong addiction, the Forum of International Respiratory Societies (FIRS), an organization composed of the world's leading international respiratory societies including American Thoracic Society (ATS) and the American College of Chest Physicians (ACCP), made the following recommendations. The position statement of the Forum of International Respiratory Societies (FIRS) on electronic nicotine delivery devices includes the following:

• The safety of electronic cigarettes has not been adequately demonstrated.

• The addictive power of nicotine and its untoward effects should not be underestimated.

• The potential benefits of electronic nicotine delivery devices, including harm reduction and as an aid to smoking cessation, have not been well studied.

• Potential benefits to an individual smoker should be weighed against harm to the population of increased social acceptability of smoking and use of nicotine.

• Health and safety claims regarding electronic nicotine delivery devices should be subject to evidentiary review.

• Adverse health effects for third parties exposed to the emissions of electronic cigarettes cannot be excluded.

• Electronic nicotine delivery devices should be restricted or banned, at least until more information about their safety is available.

• If electronic nicotine delivery devices are permitted, they should be regulated as medicines and subject to the same evidentiary review of other medicines.

• If electronic nicotine delivery devices are not regulated as medicines, they should be regulated as tobacco products.

• Research, supported by sources other than the tobacco or electronic cigarette industry, should be carried out to determine the impact of electronic nicotine delivery devices on health in a wide variety of settings.

• The use and population effects of electronic nicotine delivery devices should be monitored.

• All information derived from this research should be conveyed to the public in a clear manner.

Schraufnagel DE, Blasi F, Drummond MB, et al. on behalf of the Forum of International Respiratory Societies. Am J Respir Crit Care Med. First published online 09 Jul 2014 as DOI: 10.1164/rccm.201407-1198PP