Author: RR

The Role of Human Papillomavirus in Nongenital Cancers

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SUMMARY: Human Papilloma Virus (HPV) is a double stranded DNA virus and is the most common sexually transmitted infection in the U.S. It was responsible for over 25,000 cancers between 2004 and 2007 in the U.S. and the incidence is rapidly increasing due to changes in sexual practices. Even though the low risk HPV types such as HPV-6 and HPV-11 have been well known to cause benign lesions such as condylomata (genital warts), low grade squamous intraepithelial lesions of the cervix and laryngeal papillomas, the high risk HPV types such as HPV-16 and HPV-18 have been of major concern because of their malignant potential. Since the implication of HPV-16 and HPV-18 in cervical cancer dating back to the early 1990’s, these HPV subtypes have also been found responsible for 45-90% of oropharyngeal cancers and 90% of anal cancers. HPV in tumor tissue can be detected by immunohistochemistry testing for P16 expression and confirmed with HPV DNA PCR. Chronic immunosuppression as seen in patients with HIV and in patients undergoing solid organ transplantation, may increase the risk for HPV infections. Patients with HPV associated oropharyngeal cancer typically are younger males, tend not to smoke or drink and present with poorly differentiated, non keratinizing tumors with basaloid morphology, compared to those with HPV negative tumors. Clinical characteristics of HPV positive oropharyngeal cancer patients with best outcomes include, those with fewer than 10 pack year smoking history and lower tumor stage. Several retrospective trials as well as some small prospective studies have shown that HPV positive oropharygeal cancers when treated with chemoradiation have significantly higher response rates, progression free survival, overall survival and better local and regional disease control. In the TAX 324 randomized phase III trial, patients received induction treatment with 3 cycles of TAXOTERE®, Cisplatin and 5-Fluorouracil (5-FU) or Cisplatin and 5-FU followed by chemoradiation with concurrent PARAPLATIN® (Carboplatin). Even though the 3 drug induction treatment group had superior outcomes compared to those who received 2 drug induction regimen in the intent to treat population, on retrospective analysis, patients with HPV positive oropharyngeal cancer had a significantly longer 5 year progression free survival (78% vs 28%) and overall survival, with an 80% reduction in mortality (HR=0.20, P<0.0001), compared to HPV negative patients, regardless of induction treatment. Other studies have shown that HPV positive patients who undergo surgery alone for oropharyngeal cancer do not appear to reap these favorable benefits, suggesting that the improved prognosis in the HPV positive patients with oropharyngeal cancer is related to chemotherapy and radiation. It also appears that HPV positive patients with oropharyngeal cancer have a better prognosis with treatment when their tumors are P53 wild type and express P16. With regards to EGFR and P16, there appears to be an inverse correlation between P16 and EGFR expression and patients with tumors expressing P16 and not EGFR have a significantly higher 5 year disease free and overall survival compared to those whose tumors overexpress EGFR but not P16. This information may have significant therapeutic implications and studies are underway trying to address this group of patients with targeted and less intense treatments. It should be noted that HPV positive status has a favorable prognostic value only for oropharyngeal primary cancers and not for other cancers of the head and neck.

With regards to anal carcinoma, there appears to be a relationship between cervical, anogenital and oropharyngeal cancer suggesting a genital-anal-oral transmission of HPV. Patients with HIV infection have a higher risk of developing HPV associated anal carcinoma and antiretroviral therapy does not decrease this risk. Anal Pap test is recommended annually for high risk patients including those with a history of anogental warts and women with abnormal cervical or vulvar cytology. For patients with anal carcinoma, positive HPV status does not confer a favorable prognosis as is the case for patients with oropharygeal carcinoma. GARDASIL®, a quadrivalent vaccine targeting HPV-6,11,16 and 18 as well as CERVARIX®, a bivalent vaccine targeting HPV-16 and 18 are presently available in the U.S. They are recommended for both females and males at an age as early as 9 years and given as a 3 shot series, to prevent HPV related Cervical Intraepithelial lesions/cervical cancer and genital warts/Anal Intraepithelial Neoplasia respectively. The authors conclude that HPV infection and associated malignancies are preventable and attempts should be made to eradicate this virus. Zandberg DP, Bhargava R, Badin S, et al. CA Cancer J Clin 2013;63:57-81

A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma Updated results

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SUMMARY: The authors in this study took a novel approach and tested a combination of two vaccines in patients with metastatic pancreatic adenocarcinoma. Traditional vaccination against specific bacterial and viral infections involves the injection of the specific weakened bacteria/virus or a structural component of the bacteria or virus. The body then mounts an immune response and is ready to respond to an infection associated with that specific bacteria or virus. Use of vaccines in cancer treatment is based on the same principle. The two vaccines studied were GVAX and CRS-207. GVAX is an allogeneic whole cell vaccine developed from pancreatic cancer cell lines. These cancer cells are irradiated, to prevent them from dividing and are genetically modified to secrete GM-CSF (Granulocyte Macrophage Colony Stimulating Factor). GM-CSF is important for the growth and activation of dendritic cells also known as Antigen Presenting Cells. This vaccine when injected attracts the dendritic cells to the vaccine injection site and the dendritic cells in turn, pick up the antigens from the vaccine and present them to the patient’s immune system. The immune system then mounts a response by activating tumor specific T-cells. This vaccine therefore theoretically boosts the body’s immune system to fight the patient’s tumor, without causing collateral damage. The second vaccine CRS-207 is live-attenuated (weakened) Listeria monocytogenes bacterium which expresses mesothelin and stimulates innate and adaptive immunity. It is genetically engineered to elicit an immune response against the tumor-associated antigen mesothelin, which has been shown to be expressed at higher levels on pancreatic cancer cells than on normal cells. Previous studies have demonstrated that survival can be improved by induction of mesothelin specific T-cell responses. In this study, 90 patients with metastatic pancreatic adenocarcinoma were randomly assigned in a 2:1 ratio to receive two doses of GVAX followed by four doses of CRS-207 or six doses of GVAX alone. Treatment was given every 3 weeks and low-dose CYTOXAN® (Cyclophosphamide) was given IV, the day before GVAX in both groups, to inhibit regulatory (suppressive) T-cells. More than 80% of the patients had at least one prior treatment for metastatic disease and 50% had two or more prior treatments. The primary endpoint was overall survival. Secondary endpoints included safety, clinical and immune responses. At a planned interim analysis, the median overall survival was 6.1 months with the combination of two vaccines vs 3.9 months with GVAX alone (HR=0.54, P=0.011), a 46% reduction in risk of death with the combination immunotherapy. The median overall survival in patients who received three total doses which included at least two doses of GVAX and at least one dose of CRS-207 was 9.7 months compared to 4.6 months for GVAX alone (HR=0.44, P=0.0074), a 56% reduction in the risk of death. In the subgroup of patients who had had two or more prior chemotherapy regimens, combination immunotherapy given as third line therapy or greater resulted in a median overall survival of 5.1 months vs 3.7 months with GVAX alone (HR=0.34, P=0.001), a 66% reduction in risk of death. Stabilization of tumor marker CA19-9 was seen in 32% of patients receiving combination immunotherapy vs 13% in those who received GVAX alone (P=0.06). The one year survival probability doubled with the dual vaccine with an estimated one year survival of 24% for the combination immunotherapy group and 12% for the GVAX alone group. Toxicities included local reactions after GVAX and transient fevers, chills, and lymphopenia after CRS-207 administration. The authors concluded that immunotherapy with a combination of two vaccines improved overall survival in patients with metastatic pancreatic carcinoma, who have failed prior therapies. Le DT, Wang-Gillam A, Picozzi V, et al. J Clin Oncol 32, 2014 (suppl 3; abstr 177)

RAINBOW A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE)

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SUMMARY: It is estimated that there were approximately 21,600 new cases and 10,990 deaths from gastric cancer in the United States in 2013. The biology of gastric cancer appears to be different in different parts of the globe. Following progression after first line treatment for metastatic disease, the median survival is approximately 3 months. Ramucirumab is a human IgG1 monoclonal antibody that inhibits VEGF-receptor 2, unlike AVASTIN® (Bevacizumab) which inhibits VEGF-A. The RAINBOW study is an international, placebo-controlled, double-blind, phase III trial in which 665 patients with metastatic gastroesophageal junction or gastric adenocarcinoma, who had disease progression on or within 4 months after first-line platinum and fluoropyrimidine-based combination therapy, were included. Patients were randomly assigned to receive TAXOL® (Paclitaxel) 80 mg/m2 given on D1, 8, 15 along with Placebo (N=335) or the same dose and schedule of TAXOL® given along with Ramucirumab 8 mg/kg IV every 2 weeks (N=330), of a 28 day cycle. Treatment was continued until disease progression or unacceptable toxicities were noted. The primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR) and Time To Progression (TTP). The median OS for the combination of Ramucirumab and TAXOL® was 9.6 months compared to 7.4 months for Placebo and TAXOL® (P=0.016; HR=0.81), resulting in a 19% reduction in the risk of death with the Ramucirumab and TAXOL® combination. The secondary endpoints favored the Ramucirumab and TAXOL® combination as well. The median PFS was 4.4 months and 2.9 months (P<0.0001; HR=0.63), ORR was 28% and 16% (P<0.0001) and median TTP was 5.5 months and 3 months with the Ramucirumab and TAXOL® combination vs Placebo and TAXOL® combination respectively. As one would expect, treatment related adverse events were seen more frequently in the Ramucirumab and TAXOL® combination group. Significant were neutropenia, hypertension, fatigue and asthenia. The incidence of febrile neutropenia in the two treatment groups was however comparable (3.1% vs 2.4%). The authors concluded that the combination of Ramucirumab and TAXOL® significantly improved both progression-free and overall survival, with significantly improved disease control rates, in patients with metastatic gastroesophageal junction or gastric adenocarcinoma. Wilke H, Van Cutsem E, Oh SC, et al. J Clin Oncol 32, 2014 (suppl 3; abstr LBA7)

 

Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer a meta-analysis of individual patient data from randomised trials

RR

SUMMARY: Bisphosphonates are presently indicated for the treatment of osteoporosis. The approved bisphosphonates in the U.S. include FOSAMAX® (Alendronate), BONIVA® (Ibandronate), ACTONEL® (Risedronate) and RECLAST® (Zoledronic acid). Several trials conducted over the past 2 decades have suggested that bisphosphonates may have anti proliferative effect in patients with breast cancer. Data from several Women's Health Initiative (WHI) studies involving more than 150,000 healthy postmenopausal women, of whom 2216 used oral bisphosphonates, revealed that women taking bisphosphonates for osteoporosis had a 32% reduction in invasive breast cancer. The AZURE investigators conducted a study to determine whether the addition of RECLAST® (Zoledronic acid) to standard adjuvant therapy would improve disease outcomes in patients with early-stage breast cancer. They noted that in the subset analysis, the addition of RECLAST® significantly improved disease free survival and overall survival in postmenopausal patients, independent of estrogen receptor status, tumor stage, and lymph node involvement (N Engl J Med 2011;365:1396-1405). With this background, the authors belonging to the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), conducted a meta-analysis and reviewed data from 15 years of bisphosphonate trials, which included 36 trials of adjuvant bisphosphonates in breast cancer and involved over 17,000 pre and postmenopausal women. RECLAST® (Zoledronic acid) and Clodronate were the most common bisphosphonates used in these trials. The primary outcomes analyzed were time to distant recurrence, local recurrence, new second primary breast cancer (ipsilateral or contralateral), time to first distant recurrence (ignoring any previous locoregional or contralateral recurrences), and breast cancer mortality. Planned subset analyses included site of recurrence, site of first distant metastasis (bone vs other), menopausal status (pre, peri and post) type of bisphosphonate (aminobisphosphonates such as RECLAST® or Clodronate) and drug schedule of bisphosphonate therapy (for bone protection vs advanced cancer). Adjuvant bisphosphonates resulted in a 34% reduction in the risk of bone recurrence (P = 0.00001) and a 17% reduction in the risk of breast cancer death (P =0.004). This benefit was seen regardless of estrogen receptor status, nodal status or whether chemotherapy was used or not. Bisphosphonates had no significant impact on non-breast cancer related deaths, contralateral breast cancer or loco-regional recurrence. In this meta-analysis, all these benefits were only seen in postmenopausal women and premenopausal women had no benefit on any disease outcomes with bisphosphonates. The authors emphasized that low estrogen environment as is seen in postmenopausal women, or women rendered menopausal by suppression of ovarian function is a prerequisite for adjuvant bisphosphonate activity. Based on this large meta-analysis, the authors recommended the use of RECLAST® once every six months or oral Clodronate, where available. Because of paucity of data, they do not recommend the use of weekly dose of oral bisphosphonates, often used to prevent osteoporosis, to achieve these benefits. Coleman R, Gnant M, Paterson A, et al. San Antonio Breast Cancer Symposium 2013; San Antonio, TX. Abstract S4-07.

Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID) Results on long-term survival

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SUMMARY: The role of Somatostatin analogs such as SANDOSTATIN® (Octreotide) for symptom control in patients with gastrointestinal and pancreatic NeuroEndocrine Tumors (NETs) is well established. SANDOSTATIN® also demonstrated antiproliferative activity in controlling tumor growth of well-differentiated metastatic midgut NETs (Carcinoid), by lengthening the Time to Tumor Progression (TTP), when compared with placebo (PROMID Study). Whether SANDOSTATIN® prolongs Overall Survival (OS) remained unclear. The study investigators now reported the long term follow up data from the same PROMID trial. Between 2001 and 2008, 85 patients were randomly assigned to receive either SANDOSTATIN® LAR (N=42) or Placebo (N=43). On disease progression, patients in the placebo group were allowed to crossover and receive SANDOSTATIN® LAR. Outcomes in patients with Hepatic tumor Load (HL – percentage of liver replaced by malignancy) at study entry of 10% or less, was compared to those whose HL was more than 10%. The median OS by January 2013 in the Placebo arm was 84 months whereas the median OS in the SANDOSTATIN® LAR group was not reached, suggesting that the OS in this group will exceed 84 months and therefore a longer follow up would be needed. Patients with HL 10% or less benefited the most whereas those with high HL did not have OS benefit with SANDOSTATIN® LAR. The authors concluded that SANDOSTATIN® LAR prolongs TTP as well as OS in patients with metastatic midgut NETs, carrying a Hepatic Load of 10% or less. Arnold R, Wittenberg M, Rinke A, et al. J Clin Oncol 31, 2013 (suppl; abstr 4030)

Baseline Selenium Status and Effects of Selenium and Vitamin E Supplementation on Prostate Cancer Risk

RR

SUMMARY: Selenium and Vitamin E Cancer Prevention Trial (SELECT), is a multicenter, randomized, placebo-controlled trial, conducted by the SWOG cooperative group, that involved more than 35,000 men. Participants were randomized to receive either, a) Selenium and Vitamin E, b) Selenium and a placebo, c) Vitamin E and a placebo or d) Two placebos. The purpose of this trial was to determine if high dose vitamin E (400 IU/day) and/or Selenium (200 mcg/day) supplements could decrease the incidence of prostate cancer. The level/concentration of Selenium in participants toenail clippings was measured at the time of study participation and the goal was to also determine whether Selenium supplements would benefit the subset of participants with low Selenium levels at baseline. Both Vitamin E and Selenium are antioxidants and Vitamin E rich foods include vegetables, vegetable oils, nuts, and egg yolks whereas Selenium a nonmetallic trace element is found in rice, wheat, seafood, meat, and Brazil nuts. The SELECT trial, which began in 2001, was stopped early in 2008, as Selenium and Vitamin E, taken alone or together for an average of five and a half years did not decrease the incidence of prostate cancer. In 2011, an update on the SELECT trial data suggested that men who were randomized to the vitamin E alone had a 17 percent increased risk of prostate cancer compared to those men taking placebo. The authors in this case–cohort study continued follow up of the SELECT trial participants and with the Selenium levels data from toenail clippings, compared the effect of Selenium and Vitamin E, taken either alone or together, on the risk of prostate cancer, among 1739 men who were diagnosed with prostate cancer, of whom 489 participants developed high-grade prostate cancer. The control group for comparison was a random sample of 3117 men without prostate cancer and they were matched to the cases by race and age. It was noted that an individual’s baseline Selenium level, in the absence of supplementation, was not associated with prostate cancer risk. However, in men who had high baseline Selenium levels, Selenium supplements almost doubled (91%) the risk of high grade prostate cancer (P=0.007). Conversely, Vitamin E supplements had no effect among men with high baseline Selenium levels but doubled the risk of high grade prostate cancer among men with low baseline Selenium levels. Frankel et al. in an accompanying editorial point out that the dose of Vitamin E in the SELECT trial was significantly higher (400 IU/day) than the dose that was selected in the Alpha-Tocopherol Beta Carotene (ATBC) Cancer Prevention trial (50 IU/day), a study that was designed to test Vitamin E and beta carotene for lung cancer prevention in smokers. In the ATBC trial, a decrease in the incidence of prostate cancer incidence was observed, although this was a secondary finding and this study was not designed to determine prostate cancer risk. They comment that high doses of Vitamin E (Alpha-Tocopherol), suppresses the more potentially beneficial serum Gamma-Tocopherol which is the prevalent dietary form of Vitamin E in the United States. Selenium deficiency in the U.S. is not common and any benefit with Selenium supplements can only be seen in those who are Selenium deficient and high doses may be detrimental. The authors concluded that in the SELECT trial, the combination of both Vitamin E and Selenium did not reduce the risk of prostate cancer or any other cancer or heart disease and was in fact harmful for a significant number of individuals. Therefore, men 55 years of age or more should avoid Vitamin E or Selenium supplements at doses that exceed the recommended dietary intake. Kristal AR, Darke AK, Morris JS, et al. J Natl Cancer Inst; First published online 22 February 2014, doi: 10.1093/jnci/djt456

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism a pooled analysis of the EINSTEIN-DVT and PE randomized studies

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SUMMARY: XARELTO® (Rivaroxaban) is an oral, direct inhibitor of Factor Xa. Two previously published randomized studies concluded that XARELTO® was noninferior to the standard anticoagulation therapy (administration of heparin overlapped and followed by Vitamin K Antagonist), for most patients with Venous ThromboEmbolism. Further, XARELTO® in these studies also had a better safety profile compared to standard anticoagulant therapy. The authors in this pooled analysis combined the data from 2 identically designed studies, EINSTEIN-DVT and EINSTEIN-PE in which XARELTO® was compared to standard anticoagulation therapy, in patients with DVT and PE respectively. The goal of this study was to provide a more accurate estimate of the efficacy and safety of XARELTO® in elderly patients and cancer patients in whom Vitamin K Antagonists (VKA) such as COUMADIN® (Warfarin) can be associated with a higher complication rate. In addition, the study included analysis of outcomes with XARELTO® in patients with previous VTE and in those presenting with extensive thrombosis. Of the 8282 patients with VTE randomized in the pooled analysis, 4151 patients received XARELTO® and 4131 patients received LOVENOX® (Enoxaparin) / Vitamin K Antagonists. In both pooled studies, patients in the XARELTO® group received a dose of 15 mg PO BID for 21 days, followed by 20 mg PO QD whereas patients assigned to the standard anticoagulation therapy group received LOVENOX® subcutaneous at a dose of 1.0 mg/kg BID and either oral Warfarin or Acenocoumarol started within 48 hours after randomization and patients continued treatment for 3, 6, or 12 months, as determined by the local Health Care Providers. INR was closely monitored and maintained between 2-3. On final review, the analysis suggested that XARELTO® resulted in efficacy similar to standard anticoagulation therapy, with a noninferiority P<0.001. The pre-specified principal safety outcome was clinically relevant bleeding and major bleeding was observed in 40 patients belonging to the XARELTO® group and in 72 patients belonging to the standard anticoagulation therapy group (HR=0.54; P= 0.002). Similar benefits in the efficacy and safety were seen in the key subgroups evaluated, which included elderly fragile patients, cancer patients, patients presenting with extensive thrombosis and those with a history of recurrent VTE. The authors concluded that the incidence of major bleeding with XARELTO® was significantly less, particularly in the high risk group of patients, when compared to standard anticoagulation therapy and may therefore have a safety advantage, without compromising efficacy. Prins MH, Lensing AW, Bauersachs R, et al. Thrombosis Journal 2013;11:21

 

 

Improved Survival with Bevacizumab in Advanced Cervical Cancer

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SUMMARY: Cervical cancer is the fourth most common cancer affecting women, worldwide. It is also the fourth most common cause of cancer death. With the availability of widespread screening techniques and HPV vaccination in the U.S., the incidence of cervical cancer is declining. Treatment of advanced cervical cancer continues to be a challenge. To address this further, the authors in this study evaluated the benefit of adding AVASTIN® (Bevacizumab) to conventional chemotherapy regimens, for patients with advanced cervical cancer. AVASTIN®, a humanized Vascular Endothelial Growth Factor (VEGF) targeted monoclonal antibody, has demonstrated single-agent activity in heavily pretreated patients with recurrent cervical carcinoma in phase II trials. In this randomized study, 452 enrolled patients with metastatic, persistent or recurrent cervical cancer received one of the four treatment regimens using a 2×2 factorial design. The four treatment groups included a) Cisplatin 50 mg/m2 plus TAXOL® (Paclitaxel) 135 or 175 mg/m2 (N=114), b) HYCAMTIN® (Topotecan) 0.75 mg/m2 given on D1 thru D3 plus TAXOL® 175 mg/m2 given on Day 1 (N=111), c) Cisplatin 50 mg/m2 plus TAXOL® 135 or 175 mg/m2 given along with AVASTIN® 15mg/kg on Day 1 (N=115) and d) HYCAMTIN® 0.75 mg/m2 given on D1 thru D3 plus TAXOL® 175 mg/m2 given on Day 1, along with AVASTIN® 15mg/kg on day 1 (N=112). Treatment was given every 21 days until disease progression, the development of unacceptable toxicities or a complete response was noted. The primary end point was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Response Rate (RR). When outcomes were analyzed, HYCAMTIN® based chemotherapy was not superior to Cisplatin based chemotherapy, regardless of prior exposure to Cisplatin. The addition of AVASTIN® to chemotherapy resulted in a significantly longer median Overall Survival (17 vs 13.3 months; HR=0.71; P=0.004), significantly longer median PFS (8.2 vs 5.9 months; HR=0.67; P=0.002) and RR (48% vs 36%; P=0.008), compared to combination chemotherapy alone. The benefit with added AVASTIN® was noted in all subgroups regardless of age, race, performance status and prior platinum exposure. Treatment was in general well tolerated without significant reduction in quality of life. As was seen in other tumor types, AVASTIN® based chemotherapy regimen was associated with a higher incidence of hypertension and thromboembolic events. The authors concluded that the addition of AVASTIN® to combination chemotherapy significantly decreased the risk of death in patients with recurrent, persistent, or metastatic cervical cancer. Tewari KS, Sill MW, Long HJ, et al. N Engl J Med 2014; 370:734-743

Impact of More Restrictive Blood Transfusion Strategies on Clinical Outcomes A Meta-analysis and Systematic Review

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SUMMARY: The traditional hemoglobin trigger to recommend blood transfusions for majority of the Health Care Providers is between 7.5 and 9 g/dl. The clinical rationale is based on the premise that increasing Hgb levels increases blood oxygen content and possible oxygen delivery to the tissues. However, there are no randomized trials validating improved oxygen delivery to tissues or better clinical outcomes in any setting at this hemoglobin transfusion trigger. The authors in this provocative study conducted a comprehensive research and performed a Primary and Secondary meta-analysis. In their primary meta-analysis, they reviewed the pooled data from 3 randomized clinical trials with 2364 patients and in these trials, a less than 7g/dl hemoglobin as a transfusion trigger (restrictive transfusion strategy) was compared with a more liberal transfusion strategy and outcomes were evaluated. These endpoints included mortality, acute coronary syndrome, pulmonary edema, infections and re-bleeding risk. The combined data from these 3 trials showed that a restrictive transfusion strategy resulted in a 26% mortality reduction in hospitalized patients, 20% reduction in total mortality, 36% reduction in the risk of re-bleeding, 56% reduction in acute coronary syndrome, 52% reduction in the incidence of pulmonary edema and 14% reduction in bacterial infections, compared with a more liberal transfusion strategy. The secondary meta-analysis evaluated patients in 16 trials (these were excluded from the primary meta-analysis) that used a less restrictive transfusion trigger (hemoglobin transfusion triggers of 7.5-10g/dl) and the authors noted that outcomes were not improved with a more liberal transfusion strategy. Further it was also noted that several observational studies have shown that Hgb levels of 5-6g/dl was well tolerated in normovolemic patients without effecting oxygen delivery. Contrary to clinical presumptions, these counter-intuitive findings can be explained based on sound physiologic principles. Normovolemic hemodilution following administration of crystalloid or colloid solutions, to replace blood loss, has been associated with a reduction in systemic vascular resistance, increase in cardiac output, coronary and cerebral blood flow and synthesis of 2,3-diphosphoglycerate in red blood cells thus maintaining movement of oxygen from red blood cells to body tissues. Liberal blood transfusions may in fact impair oxygen uptake by vital tissues by increasing the blood viscosity and the resulting loss of RBC function during preservation and storage of blood. Studies have also shown that in patients with gastrointestinal bleeding, restrictive transfusion strategy results in a lower portal blood pressure and less recurrent bleeding, as higher blood pressures might disrupt a thrombus plug. The authors following this clinically relevant meta-analysis concluded that restrictive transfusion strategy resulted in better outcomes and transfusion triggers should be evidence based. Salpeter SR, Buckley JS and Chatterjee S. The American Journal of Medicine 2014;127:124-131

Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia

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SUMMARY: Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s tyrosine kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the BCR, Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, NF-κB pathways and resulting B-cell activation and proliferation. IMBRUVICA® (Ibrutinib, PCI-32765) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). The FDA granted accelerated approval of IMBRUVICA® for the treatment of patients with Chronic Lymphocytic Leukemia (CLL) who had received at least one prior therapy. This approval was based on the outcomes in a select group of 48 patients who were a part of a larger group of 85 patients, enrolled in a multicenter single arm phase Ib/II trial. The median age was 67 years and 71% were male. Patients had a median number of 4 prior treatments and had an ECOG PS of 0-1. Patients in this group received IMBRUVICA® 420 mg PO daily until disease progression or unacceptable toxicity. The overall response rate was 58.3% as assessed by an independent review committee. No complete responses were seen and the response duration ranged from 5.6 to over 24 months. This analysis did not include data from those patients enrolled in the trial who received IMBRUVICA® 840 mg PO daily or those with Small Lymphocytic Lymphoma (N=37). The most common toxicities included fatigue, myalgias and arthralgias, cytopenias, nausea, diarrhea, fever and rash. Transient asymptomatic increase in lymphocyte count with resolution of lymphadenopathy and splenomegaly was common but resolved with continued treatment. The confirmatory RESONATE trial is a multicenter, randomized, open-label Phase III study in which single agent IMBRUVICA® was compared to single agent ARZERRA® (Ofatumumab) in patients with relapsed or refractory CLL or Small Lymphocytic Lymphoma . This was a part of the requirement by the FDA. Enrolled patients had measurable nodal disease and were not eligible for treatment with purine analog-based therapy. In this study, 391 patients who had received at least one prior therapy, were enrolled and randomized to receive 420 mg of IMBRUVICA® orally once daily or ARZERRA® given intravenously. Treatment was given over a period of 24 weeks until disease progression or unacceptable toxicity. Patients randomized to the ARZERRA® group on disease progression were allowed to receive treatment with IMBRUVICA®. The primary endpoint of this study was progression-free survival and the secondary endpoint was overall survival. Following recommendations from the Independent Data Monitoring Committee (IDMC), the study was stopped earlier, as the primary endpoint as well as an important secondary endpoint of the study were met. At the planned interim analysis, patients in the IMBRUVICA® group showed a statistically significant improvement in progression-free survival, the primary endpoint of the study as well as a statistically significant improvement in overall survival, the secondary endpoint of the trial. This data confirmed the efficacy of IMBRUVICA® and gives patients with CLL, an important new treatment option. Byrd JC, Furman RR, Coutre SE, et al. N Engl J Med 2013; 369:32-42