SUMMARY: The US Food and Drug Administration on January 29, 2015, approved Ibrutinib (IMBRUVICA®) for the treatment of patients with Waldenstrom Macroglobulinemia (WM). Waldenstrom Macroglobulinemia is classified as a LymphoPlasmacytic Lymphoma (LPL) according to the Revised European American Lymphoma (REAL) and WHO (World Health Organization) classifications. It is estimated that about 1500 new cases of WM will be diagnosed each year in the US. Chromosome 6q deletion detected by FISH technique on bone marrow evaluation, is seen in 40-50% of the patients with WM. Whole genome sequencing of lymphoplasmacytic cells has revealed activating somatic mutations in MYD88 (L265P) and CXCR4 genes, in Waldenstrom Macroglobulinemia (WM).
About 90% of patients with Waldenstrom Macroglobulinemia demonstrate a mutation in chromosome 3p (MYD88 L265P), which is specific to WM and may be an early oncogenic event in WM pathogenesis.. It appears that MYD88 L265P promotes malignant cell proliferation via the Bruton’s Tyrosine Kinase (BTK) signaling pathway. Mutations in CXCR4 gene are present in 30% of patients with WM, and their expression induces BTK activity and may confer resistance to BTK inhibitors. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). Preliminary studies in WM patients have revealed that IMBRUVICA® prevents the binding of MYD88 L265P (mutated gene) to BTK thereby selectively killing tumor cells. On the other hand it was noted that a major response to IMBRUVICA® was less likely when mutations in CXCR4 gene were present in the tumor cells. With this molecular understanding of WM, the authors enrolled 63 patients with relapsed/refractory symptomatic WM and were treated with IMBRUVICA®, 420 mg PO daily for 2 years or until disease progression or unacceptable toxicity. Anemia was main indication for treatment initiation (87.3% of patients) and the mean baseline hemoglobin level was 10.5 g/dL, mean serum IgM level was 3610 mg/dL, 70% had bone marrow involvement and 60% of patients had lymphadenopathy. 
Sanger sequencing was used to determine MYD88 and CXCR4 mutations in the bone marrow lymphoplasmacytic cells. At best response, the median serum IgM levels declined to 1340 mg/dL (P<0.00001), median hemoglobin rose to 12.6 g/dL, (P<0.00001). At 6 months, bone marrow assessment post treatment, demonstrated a reduction in WM disease involvement from 70% to 45% (P=0.0006). With a median follow up at 6 cycles, the best overall response rate was 81% and a median time to response was 4 weeks. In patients who underwent tumor sequencing, mutations in CXCR4 gene impacted response rates. The major response rate for patients with wild-type CXCR4 gene was 77% compares to 30% in those with CXCR4 mutations (p=0.018). Further, patients with wild-type CXCR4 also had increased peripheral lymphocytosis following treatment with IMBRUVICA® compared to those with CXCR4 mutations (P=0.001). The most common more than grade 2 treatment related toxicities included thrombocytopenia (14.3%) and neutropenia (19.1%). The authors concluded that IMBRUVICA® is highly active in patients with relapsed or refractory Waldenstrom Macroglobulinemia, with rapid reductions in serum IgM level and improved hemoglobin levels. The presence of CXCR4 mutations negatively impact response rates in this patient group. Treon SP, Tripsas CK, Yang G, et al. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 251.
Category: Hem/Onc Updates
Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer
SUMMARY: The U. S. Food and Drug Administration on February 13, 2015 approved Lenvatinib (LENVIMA®) for the treatment of patients with locally recurrent or metastatic, progressive, RadioActive Iodine (RAI)-refractory Differentiated Thyroid Cancer (DTC). The American Cancer Society estimates that about 62,450 new cases of thyroid cancer will be diagnosed in the United States for 2015 and about 1,950 patients will die of the disease. Thyroid cancer is the most prevalent endocrine malignancy and is classified into three histological groups – Differentiated Thyroid Cancers (94%) which include Papillary (80%), Follicular (11%) and Hürthle cell (3%) histologies, Medullary Thyroid Carcinoma (MTC) representing 4% and Anaplastic (undifferentiated) Thyroid Carcinoma (ATC) representing about 2%. Approximately 20% of the patients with DTC develop local recurrence and 10% develop metastatic disease at 10 years following surgery, radioiodine ablation and TSH suppressive therapy. These tumors lose avidity for iodine and are considered RadioActive Iodine (RAI) refractory.
The discovery of genetic alterations in the MAP Kinase pathway as well as the PI3K (Phosphatidylinositol-3-Kinase)-AKT-mTOR pathway in thyroid tumors, has lead to the development of Tyrosine Kinase Inhibitors (TKI’s), to target these activated pathways. LENVIMA® is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR)1-3, Fibroblast Growth factor Receptor (FGFR)1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1 thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting by FGFR and PDGFR beta. 
The SELECT trial is a double-blind, multicenter, phase III study in which 392 patients with advanced RAI-refractory Differentiated Thyroid Cancer (DTC) were randomly assigned in a 2:1 ratio to receive LENVIMA® 24 mg PO daily in 28-day cycles (N=261) or placebo (N=131). Both treatment groups were well balanced and pretreatment with one prior Tyrosine Kinase Inhibitor (TKI) was allowed. Patients in the placebo group were allowed to cross over and receive open-label LENVIMA®, at the time of disease progression. The primary end point was Progression Free Survival (PFS) and secondary end points included Response Rate, Overall Survival, and safety. 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). This benefit in PFS associated with LENVIMA® was observed in all pre-specified subgroup of patients including those who had received one prior treatment with a TKI. The objective response rate with LENVIMA® was 64.8% versus 1.5% with placebo (P<0.001) and the median overall survival was not reached in either group. The most frequently reported grade 3 or more adverse events in the LENVIMA® group included hypertension (42.9%) and proteinuria (10%). Approximately 14% of the patients in the LENVIMA® group discontinued the drug due to adverse effects. Exploratory biomarker analyses were performed for BRAF and RAS mutations on tumor tissue and it was noted that LENVIMA® benefitted patients regardless of BRAFor RAS mutation status. The authors concluded that LENVIMA® decreased the risk of disease progression by 79% as compared with placebo and was associated with significant improvements in objective Response Rate among patients with RAI-refractory thyroid cancer. NEXAVAR® (Sorafenib), another multitargeted TKI, is presently available for this group of patients and therefore proper sequencing of LENVIMA® and NEXAVAR® remains unknown although it appears that LENVIMA® has a markedly higher Progression Free Survival compared to NEXAVAR®. Schlumberger M, Tahara M, Wirth LJ, et al. N Engl J Med 2015; 372:621-630
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 cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18) a randomised phase 2 study
SUMMARY:The U. S. Food and Drug Administration on February 3, 2015 granted accelerated approval to IBRANCE® (Palbociclib), for use in combination with FEMARA® (Letrozole), for the treatment of postmenopausal women with Estrogen Receptor (ER)-positive, Human Epidermal growth factor Receptor 2 (HER2) negative advanced Breast Cancer, as initial endocrine-based therapy for their metastatic disease. Approximately 60% of the breast tumors express Estrogen Receptors and these patients are often treated with anti-estrogen therapy as first line treatment.
Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. IBRANCE® is a reversible, oral, small molecule inhibitor of Cyclin Dependent Kinases (CDK) 4/6 and is the first CDK inhibitor approved by the FDA. This agent in pre-clinical studies was noted to reduce cellular proliferation of Estrogen Receptor positive Breast Cancer cell lines by blocking progression of cells from G1 into S phase of the cell cycle and was also noted to be synergistic with anti-estrogens. The approval of IBRANCE® was based on an open-label, randomized, multicenter, phase II study which included postmenopausal women with ER-positive, HER2-negative, advanced (locally advanced or metastatic) Breast Cancer who had not received previous systemic treatment for advanced disease. This trial enrolled and randomly assigned 165 patients, to receive either IBRANCE® 125 mg PO daily for 21 consecutive days, followed by 7 days off treatment) plus FEMARA® (2.5 mg PO daily continuously throughout the 28-day cycle (N=84) or FEMARA® alone (N=81). Among the 165 patients, 43% had received chemotherapy and 33% had received anti-hormonal therapy as a neoadjuvant or adjuvant treatment. Fortynine percent (49%) of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had stage IV disease, 48% had visceral disease and 17% had bone only disease. The primary endpoint was investigator-assessed Progression Free Survival. The median PFS was 20.2 months in the IBRANCE® plus FEMARA® group and 10.2 months in the FEMARA® alone group (HR=0.488, P=0•0004). In patients with measurable disease, the Overall Response rate was higher in the IBRANCE® plus FEMARA® group compared to the FEMARA® alone group (55% versus 39%, P=0.04). The median duration of response for those who had a partial or complete response was 20.3 months with a combination of IBRANCE® plus FEMARA® vs 11.1 months with FEMARA® alone. The most common Grade 3–4 adverse events in the IBRANCE® plus FEMARA® group were neutropenia and leucopenia but without any cases of neutropenic fever. Unlike chemotherapy, the duration of neutropenia was brief with rapid recovery of blood counts. The authors concluded that the addition of IBRANCE® to FEMARA® significantly improved Progression Free Survival in women with advanced Estrogen Receptor positive and HER2-negative breast cancer. This combination may therefore be a reasonable treatment option in this patient group, soon after metastatic disease is diagnosed. Biomarkers expression (cyclinD1 amplification and/or loss of p16) had no impact on outcomes suggesting that the biomarker for IBRANCE® may be the Estrogen Receptor itself, rather than CDK4/6 kinases. Finn RS, Crown JP, Lang I, et al. Lancet Oncol 2015; 16:25-35
Pre- and Post-diagnosis Physical Activity, Television Viewing, and Mortality Among Patients With Colorectal Cancer in the National Institutes of Health–AARP Diet and Health Study
SUMMARY:The American Cancer Society estimates that approximately 137,000 new cases of colorectal cancer were diagnosed in the United States in 2014 and over 50,000 died of the disease. Even though colon cancer localized to the bowel is potentially curable with surgery and adjuvant chemotherapy, advanced colon cancer is often incurable. Standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival and Overall Survival. Reducing risk of death and improving survival even further with leisure time physical activity is the topic of this discussion. The most prevalent sedentary behavior, watching TV, has been associated with poorer survival in the general population. Several studies have suggested protective effects of physical activity on cancer recurrence although this has not been conclusive. Pooled data from other studies have shown that lack of physical activity among survivors of ColoRectal Cancer (CRC) has been associated with higher mortality risk. However, the independent effects of physical activity before and after colorectal cancer diagnosis, has remained unclear and the association between watching TV and mortality in survivors of CRC has not been defined.
There are several biologic mechanisms that explain the association between sedentary life style, physical activity, and mortality. The adipose tissue in the body in addition to serving as the storage site for energy also releases adipokines, which have pro-inflammatory and anti-inflammatory properties. Physical activity decreases inflammatory adipocytokines and increases anti-inflammatory cytokines and thereby could affect cancer incidence and mortality. Also, physical activity has been shown to increase insulin sensitivity. Several studies have shown increased risk of CRC, increased angiogenesis, tumor growth, and anti-apoptotic activity with higher circulating insulin and insulin-like growth factor-1 and lower insulin-binding protein levels. Physical activity also improves cardiovascular health by lowering blood pressure. The authors in this study explored the impact of lifestyle such as moderate to vigorous intensity physical activity level and TV viewing time (sedentary life style) on ColoRectal Cancer mortality among CRC survivors, with particular attention to pre and post cancer diagnosis contributing factors. Data was collected from a large cohort of patients enrolled in the National Institutes of Health Diet and Health Study and the associations were analyzed between pre CRC diagnosis (N=3797) and post CRC diagnosis (N= 1759) life styles (physical activity and TV watching) and overall and disease-specific mortality. It was noted that patients who had 7 or more hours of weekly leisure physical activity before their diagnosis of CRC had a 20% lower risk of all-cause mortality compared to those who had a sedentary life style and were not engaged in any leisure time activity (HR=0.80; P=0.02). Patients who were engaged in 7 or more hours of weekly leisure physical activity post CRC diagnosis had a 31% lower risk of all-cause mortality compared to those who reported no activity (HR=0.69; P=0.006). This benefit was noted independent of pre-diagnosis activity. Amongst those who reported sedentary lifestyle, patients who spent 5 or more TV hours per day before CRC diagnosis had a 22% increased risk in all-cause mortality compared to those who watched no more than 2 hours of TV per day (HR=1.22; P=0.002). A similar trend of increased risk of all-cause mortality was seen in those who spent more TV hours, post diagnosis although this was not statistically significant. The authors concluded that in patients with CRC, leisure time physical activity was inversely associated with all-cause mortality, whereas more TV hours was associated with increased mortality risk. Health Care providers should therefore proactively promote increasing physical activity and minimizing TV hours, among survivors of ColoRectal Cancer. Arem H, Pfeiffer RM, Engels EA, et al. J Clin Oncol 2015; 33:180-188
Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302) final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study
SUMMARY: Prostate Cancer is the most common cancer in American men and approximately 233,000 new cases were diagnosed in 2014 and close to 30,000 men died of the disease. The primary systemic intervention for patients with advanced prostate cancer is Androgen Deprivation Therapy (ADT). This can be accomplished by either surgical castration (bilateral orchicetomy) or medical castration, using LHRH (GnRH- Gonadotropin-Releasing Hormone) agonists. Majority of these patients will eventually develop progressive disease (Castrate Resistant Prostate cancer – CRPC), due to enhanced autocrine and /or paracrine synthesis of androgens or androgen precursors in the tumor microenvironment. This has lead to the development of novel compounds that decrease androgen synthesis as well as androgen signaling in patients with CRPC.
Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17A. COU-AA-302 trial is a placebo controlled, double-blind, randomized, phase III study and at the interim analyses showed that ZYTIGA® plus Prednisone significantly improved radiographic Progression Free Survival compared with placebo plus Prednisone, in men with chemotherapy-naive CRPC. The authors in this publication provided additional data on the pre-specified final analysis of the trial, which included the effect of ZYTIGA® plus Prednisone on Overall Survival, time to opiate use, and use of other subsequent therapies. In this study which included 1088 chemotherapy-naïve, asymptomatic or mildly symptomatic CRPC patients, 546 patients received ZYTIGA® 1000 mg PO plus Prednisone 5 mg PO twice daily and 542 patients received placebo plus Prednisone. The co-primary endpoints were radiographic Progression Free Survival and Overall Survival. In the final analysis, at a median follow up of 49•2 months, the median Overall Survival was 34.7 months in the ZYTIGA® group vs 30.3 months in the placebo control group (HR = 0.81, P = 0.0033). This benefit was seen across all prespecified subgroups, as well as adjusting for crossover from placebo to ZYTIGA® (HR = 0.79, P = 0.0013). The median time to opiate use for cancer-related pain was significantly prolonged in the ZYTIGA® group compared to the placebo group (33.4 vs 23.4 months, HR = 0.72, P < 0.0001). The most common grade 3 or 4 adverse events of special interest in the ZYTIGA® vs placebo group were cardiac disorders (8% vs 4%), increased ALT (6% vs < 1%), and hypertension (5% vs 3%). The authors concluded that with a median follow up of more than 4 years, treatment with ZYTIGA® in patients with chemotherapy-naive metastatic CRPC, significantly improved Overall Survival compared with Prednisone alone, with favorable toxicities. Ryan CJ, Smith MR, Fizazi K, et al. for the COU-AA-302 Investigators .The Lancet Oncology 2015; 16:152-160
Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib
SUMMARY: It is estimated that in the US, approximately 76,000 new cases of melanoma were diagnosed and close to 8000 individuals died of the disease, in 2014. The incidence of melanoma has been on the rise for the past three decades. The FDA granted accelerated approval in January 2014, for a combination of MEKINIST® (Trametinib) and TAFINLAR® (Dabrafenib), to treat patients with advanced melanoma, based on the understanding of the biological pathways of this malignancy. The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6%-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas. In the BREAK-3 randomized phase III trial, TAFINLAR® (Dabrafenib), a selective oral BRAF inhibitor demonstrated a statistically significant improvement in Progression Free Survival (PFS) and Response Rate (RR) compared to Dacarbazine (DTIC), in patients with advanced BRAF V600E/K mutated melanoma. In the BRIM 3 randomized, phase III study, ZELBORAF® (Vemurafenib), a selective oral inhibitor of mutated BRAF demonstrated significant improvement in Progression Free Survival and Overall Survival compared to Dacarbazine.
Squamous cell carcinoma’s were seen in about 6% of the patients treated with BRAF inhibitors. Paradoxical activation of the MAPK pathway in cells without a BRAF mutation has been implicated in the emergence of drug resistance and increased incidence of BRAF-inhibitor induced skin tumors. The addition of a MEK inhibitor such as MEKINIST® (Trametinib) to a BRAF inhibitor such as TAFINLAR®, has addressed some of these limitations, in previously published studies, with improvement in Progression Free Survival. MEKINIST® is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway and has been shown to significantly improve Progression Free Survival, Response Rate and Overall Survival, when compared to chemotherapy, in advanced melanoma patients with BRAF V600E/K mutations. The authors in this open label, randomized, phase III trial, evaluated the outcomes, comparing a combination of TAFINLAR® and MEKINIST® with single agent ZELBORAF® , in previously untreated and unresectable Stage IIIC or IV melanoma patients with BRAF V600E or V600K mutations. Eligible patients (N=704) were assigned in a 1:1 ratio to receive either a combination of TAFINLAR® (Dabrafenib), 150 mg PO BID and MEKINIST ® (Trametinib) 2 mg PO QD or ZELBORAF® (Vemurafenib) 960 mg PO BID, as first line therapy. The primary end point of this study was Overall Survival. Secondary end points included Progression Free Survival, Overall Response Rate, duration of response, and safety. At the preplanned interim analysis, the Overall Survival at 12 months was 72% in the combination therapy group and 65% in the single agent ZELBORAF® group (HR=0.69; P=0.005). The median Progression Free Survival was 11.4 months in the combination therapy group and 7.3 months in the ZELBORAF® group (HR=0.56; P<0.001). The objective response rate was 64% with combination therapy and 51% with single agent ZELBORAF® (P<0.001). There was no difference in the rates of severe adverse events and study drug discontinuations between the two groups. Skin cancers such as Squamous cell carcinoma and Keratoacanthoma occurred in 1% of patients in the combination therapy group and 18% of those treated with ZELBORAF® . The authors concluded that a combination of BRAF inhibitor TAFINLAR® and MEK inhibitor MEKINIST® significantly improved Overall Survival as compared with ZELBORAF® monotherapy, with a 31% relative reduction in the risk of death, in previously untreated patients with metastatic melanoma, with BRAF V600E or V600K mutations. This benefit was accomplished without increased overall toxicity. Robert C, Karaszewska B, Schachter J, et al. N Engl J Med 2015; 372:30-39
p16 Protein Expression and Human Papillomavirus Status As Prognostic Biomarkers of Non-Oropharyngeal Head and Neck Squamous Cell Carcinoma
SUMMARY: Squamous Cell Carcinoma of the Head and Neck (HNSCC) accounts for about 3-5% of all cancers in the United States. It is estimated that 55,070 people were diagnosed with Head and Neck cancer in 2014 and 12,000 patients died of the disease. The head and neck region includes the oral cavity, oropharynx, hypopharynx and larynx. Squamous Cell Carcinoma involving the head and neck region (HNSCC) is therefore a heterogeneous disease and the five year survival rate of patients with head and neck cancer depends on several factors and can be variable. Common risk factors include tobacco and alcohol use and Human PapillomaVirus (HPV) infection. Recent studies have shown that over 70% of the OroPharyngeal Squamous Cell Carcinomas (OPSCC) are caused by HPV with the HPV-16 being the predominant type present in the tumor cells.
The malignant behavior of these tumors is dependent on the expression of viral E6 and E7 oncoproteins that inactivate the tumor suppressor proteins p53 and the retinoblastoma protein (pRB), respectively. HPV positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) is more common among never smokers or light smokers and patients tend to be younger with better performance status. The pathobiology of HPV positive OroPharyngeal Squamous Cell Carcinoma (OPSCC) is different from the HPV negative OroPharyngeal Squamous Cell Carcinoma in that p53 is degraded/inactivated by viral E6 oncoprotein instead of by genetic mutation, pRB pathway is inactivated by viral E7 oncoprotein instead of Cyclin D1 amplification and p16 is overexpressed or upregulated instead of inactivation resulting from reduced negative feedback from pRB. Testing for HPV is based on several methodologies which include detection of HPV DNA by in situ hybridization (ISH) or Polymerase Chain Reaction (PCR), detection of HPV E6/E7 RNA expression by quantitative Reverse Transcriptase–PCR (qRT-PCR) and p16 protein overexpression, a surrogate marker of oncogenic HPV infection, by ImmunoHistoChemistry (IHC) staining. Both p16 overexpression testing by IHC and HPV by ISH can be easily performed on Formalin-Fixed Paraffin Embedded (FFPE) specimen whereas detection of HPV E6/E7 RNA expression, which is indicative of active viral oncogene transcription in tumor cells and is considered to be a gold standard, requires a larger tumor specimen compared with other methodologies.
The concordance rate between HPV by ISH and p16 by IHC is approximately 90% in OPSCC, whereas the prevalence and significance p16 by IHC has remained unclear for HPV infection in non-OPSCC (oral cavity, hypopharynx and larynx). It is well established however that patients with HPV-positive/p16-positive OPSCC have better outcomes compared with those with HPV-negative/p16-negative OPSCC. However, the prognostic significance of p16 overexpression in non-OPSCC patients with or without evidence of HPV infection has not been clear. The authors in this study evaluated p16 protein overexpression by IHC and HPV status by HPV ISH as potential prognostic biomarkers in non-OPSCC tumors of patients enrolled in three prospective Radiation Therapy Oncology Group (RTOG) clinical trials. Of the 1921 patient enrolled in these three trials, 683 patients with non-OPSCC tumors were eligible and 52% (N=356) of these patients were tested for p16 overexpression and overall, 19.3% were p16 positive. When OPSCC and non-OPSCC patients were compared, OPSCC patients whose tumors were p16 positive had better Progression Free Survival and Overall Survival than non-OPSCC patients with p16 positive tumors. However, patients with p16 negative OPSCC and non-OPSCC have similar inferior outcomes. The authors concluded that patients with p16 negative non-OPSCC have worse outcomes than patients with p16 positive non-OPSCC, similar to that seen in patients with OPSCC and therefore HPV infection may influence outcomes in a subset of patients with non-OPSCC as well. Better methodologies for HPV detection and correlation with p16 expression will help identify “true” HPV infection related non-OPSCC and thereby enable tailored and less intense treatment, for this favorable group of patients. Chung CH, Zhang Q, Kong CS, et al. J Clin Oncol 2014; 32:3930-3938
Aspirin for the Prevention of Recurrent Venous Thromboembolism The INSPIRE Collaboration
SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000 – 100,000 deaths. VTE is the third leading cause of cardiovascular mortality with a mortality rate of up to 25% in those with untreated acute pulmonary embolism. Even though the risk of recurrent VTE is high after anticoagulant treatment is discontinued in patients with a first unprovoked venous thromboembolism (10-30% risk of a recurrence within 5 years following cessation of anticoagulation), a significant number of these patients receive therapy for 6-12 months and are not routinely treated with long term anticoagulant therapy. This may be due to bleeding risks, cost of therapy and need for diligent monitoring while on long term anticoagulation. 
Aspirin is a non-selective, irreversible inhibitor of both COX-1 and COX-2 (Cyclooxygenases 1 and 2). It inhibits the production of Prostaglandins and Thromboxane A2 and there by decreases platelet aggregation. Both ASPIRE and WARFASA trials support the role of aspirin for the prevention of recurrent VTE in patients with an unprovoked VTE, after 6-18 months of anticoagulation therapy. These trials however were not individually powered to detect benefits of treatment for particular outcomes or subgroups of patients. The INSPIRE Collaboration involved further analysis of these trials to detect outcomes in pre-specified subgroups of patients. The intent-to-treat analysis included 1,224 patients and at a median follow up of 30.4 months, daily Aspirin given at a dose of 100mg reduced recurrent VTE events by 32% (HR=0.68; P=0.008) and this included reduction in recurrent Deep Vein Thrombosis by 34% (HR=0.66; P=0.01) and Pulmonary Embolism by 34% (HR=0.66; P=0.08), compared to Placebo. After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR=0.58; P=0.005). Subgroup analyses indicated similar relative, but larger absolute, risk reductions in men and older patients. Aspirin also reduced major vascular events by 44% (HR=0.66; P=0.002). The major bleeding rate was low at 0.5%/year for Aspirin and 0.4%/year for Placebo. The authors concluded that aspirin reduces the risk of recurrent VTE. Even though the efficacy of aspirin is inferior to that of Warfarin or the new oral anticoagulants, this data suggests that Aspirin should be strongly considered in patients with unprovoked VTE for whom long-term anticoagulation therapy with Warfarin or one of the new oral anticoagulants has to be discontinued or is not an appropriate option. Aspirin however, should not be considered a replacement option for conventional anticoagulation. Simes J, Becattini C, Agnelli G, et al. Circulation. 2014; 130:1062-1071
Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma
SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 24,050 new cases were diagnosed in 2014 and 11,090 died of the disease. KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone proteasome inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. KYPROLIS® monotherapy is presently approved in the United States for use in patients with relapsed and refractory Multiple Myeloma following a phase 2b single arm study which showed a 24% overall response rate in this patient group. REVLIMID® (Lenalidomide) given along with weekly Dexamethasone, was associated with significantly improved Progression Free Survival (PFS) when administered until disease progression, in patients with newly diagnosed Multiple Myeloma. The combination of REVLIMID® and weekly Dexamethasone is considered a reference regimen for both newly diagnosed and relapsed multiple myeloma. VELCADE® in combination with REVLIMID® and Dexamethasone showed an overall response rate of 64% and a median PFS of 9.5 months in patients with relapsed and refractory Multiple Myeloma. Based on this background the authors conducted this randomized, open label, multicenter, phase III study in which the safety and efficacy of a combination of KYPROLIS® (Carfilzomib), REVLIMID® and weekly Dexamethasone (KYPROLIS® group) was compared with a combination of REVLIMID® and weekly Dexamethasone (control group), in patients with relapsed Multiple Myeloma. Seven hundred and ninety two (N=792) patients were randomly assigned in a 1:1 ratio to KYPROLIS® group (N=396) and control group (N=396). Eligible patients included those with Multiple Myeloma who had received one to three prior treatments which included VELCADE® or REVLIMID and Dexamethasone combination, provided that they did not have disease progression during treatment with these agents. The 28 day treatment cycle consisted of KYPROLIS® IV given on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1 with a target dose of 27 mg/m2 thereafter) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, following which KYPROLIS® was discontinued. REVLIMID® 25 mg PO was given on days 1 through 21 and Dexamethasone 40 mg PO was administered on days 1, 8, 15, and 22. Patients in both treatment groups received only REVLIMID® and Dexamethasone after cycle 18 until disease progression. Antiviral and antithrombotic prophylaxis was administered to patients in both treatment groups. The primary end point was Progression Free Survival and secondary end points included Overall Survival, the rate of overall response (partial response or better), response duration, health-related quality of life, and safety. The rate of clinical benefit (minimal response or better) was an exploratory end point. The study met its primary endpoint at the time of the pre-specified interim analysis with a significant improvement in the median Progression Free Survival for those patients in the KYPROLIS® group compared to the control group (26.3 months versus 17.6 months; HR=0.69; P=0.0001). This benefit in the PFS was demonstrated across all predefined subgroups. The median overall survival was not reached in either group and the 24 month overall survival rates were 73.3% and 65.0% in the KYPROLIS® and control groups, respectively (HR=0.79; P=0.04). The overall response rates (partial response or better) were 87.1% and 66.7% in the KYPROLIS® and control groups, respectively (P<0.001). Amongst the responders, 31.8% and 9.3% of patients in the respective groups had a complete response or better and 14.1% and 4.3% had a stringent complete response. Further, patients in the KYPROLIS® group reported superior health-related quality of life. Grade 3 or higher adverse events were reported in 83.7% and 80.7% of patients in the KYPROLIS® and control groups respectively. The authors concluded that the addition of KYPROLIS® to REVLIMID® and Dexamethasone resulted in significant improvement in PFS as compared with REVLIMID® and Dexamethasone alone, in patients with relapsed Multiple Myeloma. Additional benefits in the KYPROLIS® group included higher and deep response rates, improved health-related quality of life, a favorable risk–benefit profile and a trend towards improved Overall Survival. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. N Engl J Med 2015; 372:142-152