SUMMARY:Prostate cancer is the most common cancer in American men, excluding skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, over 230,000 new cases of prostate cancer will be diagnosed in 2014 and close to 30,000 men will die of the disease. The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence.
The American Urological Association suggested that a PSA of 0.2 ng/mL or higher defines PSA failure or relapse, after Radical Prostatectomy. A PSA rise of 2 ng/ml or more above post Radiation Therapy nadir, is considered PSA failure or relapse. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Prostate cancer patients who had thought that they were cured, consequently can experience considerable mental anguish and anxiety, based on these laboratory findings. Androgen Deprivation Therapy (ADT) is often initiated following PSA only relapse with the intent of delaying disease progression although the role of ADT and optimal timing to start ADT (Immediate vs deferred ADT) in this patient population is unknown. Further, ADT can be associated with side effects such as fatigue, loss of muscle mass, impotence, anemia, osteoporosis, etc., which in turn can have a significant negative impact on an individual’s quality of life. In order to determine the significance of benefit if any, with starting ADT while patients are asymptomatic, the authors analyzed data on more than 14,000 patients included in a prospective registry called CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) and of them studied 2,022 men, who had experienced a PSA only relapse following curative surgery or radiation. These patients had clinical stage T3a,N0M0 or lower stage prostate cancer and experienced PSA only relapse (defined as PSA of 0.2 ng/mL or higher after Radical Prostatectomy or three rising PSA values one month apart following radiation treatment. Patients with symptoms, documented metastatic disease by CT scan or bone scan and ADT in the previous 12 months were excluded. Patients in the” Immediate treatment group” initiated ADT within 3 months of PSA relapse and those in the “Deferred treatment group” initiated ADT, 2 or more years after PSA relapse or when they presented with metastasis, symptoms or had a short PSA doubling time. The median age was 69 years, 34% had a Gleason score >7 and 32% received radiotherapy as primary treatment. The median time from primary treatment to PSA relapse was 27 months. Patients were followed for a median of 52.3 months after PSA relapse. The Five-year survival rate for Patients in the” Immediate treatment group” was 85.1% and for those in the “Deferred treatment group” was 87.2% with no significant difference in the all cause mortality. The 10 year survival was identical in both groups at 71.6%. The authors concluded that there is little or no survival benefit for Immediate ADT initiation compared with Deferred ADT initiation (at clinical progression or at least two years after PSA relapse) among prostate cancer patients with PSA only relapse. Therefore delaying ADT for at least 2 years after PSA relapse, following curative therapy for prostate cancer does not worsen overall survival. The findings from this large observational study will need further validation and a randomized phase III trial is underway to confirm these findings. Garcia-Albeniz X, Chan JM, Paciorek AT, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 5003)
Category: Hem/Onc Updates
Final results of a randomized phase 2 study showing the clinical benefit of quizartinib (AC220) in patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia
SUMMARY: Acute Myeloid Leukemia (AML) is generally a disease of the elderly and the average age of a patient at the time of diagnosis is about 66 years. According to the American Cancer Society, approximately 18,860 new cases of AML will be diagnosed in 2014 and 10,460 patients will die of the disease. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy. 
The fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the cell surface (transmembrane) and plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML and is detected in approximately 30% of the patients. The most common FLT3 mutation is the FLT3-ITD (Internal Tandem Duplication) mutation caused by a tandem duplication within the coding region of the gene. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations have poor outcomes with shorter remission duration and significantly decreased leukemia free and overall survival. These mutations are detected using Polymerase Chain Reaction (PCR) based molecular diagnostic DNA testing. Several therapeutic agents are being developed to target FLT3 mutations. Quizartinib (AC220) is an oral tyrosine kinase inhibitor, which has demonstrated activity in patients with both wild type FLT3 as well as those with FLT3-ITD mutations. In this randomized, open label phase II study, the authors evaluated the efficacy and safety of two different, lower dosages of Quizartinib, in patients 18 years of age or older, with FLT3-ITD positive, relapsed or refractory AML. Seventy six patients (N=76) were randomized to receive either Quizartinib 30 mg/day (Group A) or Quizartinib 60 mg/day (Group B), given orally and continuously, during a 28 day treatment cycle. Treatment was continued until relapse, intolerance or Hematopoietic Stem Cell Transplantation (HSCT). Both groups were well balanced except for age over 60 years (42% Group A, 26% Group B) and the percentage with secondary AML (8% Group A, 18% Group B). The composite Complete Remission (CRc) rate included Complete Remission (CR), Complete Remission with incomplete platelet recovery (CRp), and Complete Remission with incomplete hematologic recovery (CRi). The CRc rate in both groups A and B was 47% and the Overall Response Rate (CRc + Partial Response (PR)) was 61% in Group A and 71% in Group B. Further, 32% of patiens in Group A and 42% in Group B were able to undergo HSCT, after achieving CRc or PR. The most common treatment related adverse events were diarrhea (18%), febrile neutropenia (16%), and QT prolongation (15%). The QT prolongation rate was significantly less with lower doses of Quizartinib, as was used in this study, compared to what was noted with higher doses of Quizartinib utilized in other trials. The authors concluded that Quizartinib is highly effective in relapsed and refractory AML patients with FLT3-ITD mutations, with an acceptable safety profile. Schiller GJ, Tallman MS, Goldberg SL, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 7100)
Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) Results from the BELIEF trial
SUMMARY: Non-Hodgkin lymphoma (NHL) is one of the most common cancers in the United States and the American Cancer Society estimates that in 2014, about 70,800 people will be diagnosed with NHL in the US and close to 19,000 people will die of the disease. T cell Lymphomas are a heterogenous group of lymphoid malignancies representing less than 15% of all Non-Hodgkin Lymphomas.
Peripheral T-cell lymphoma – NOS (PTCL-Not Otherwise Specified) is the most common of the aggressive T-cell lymphoma subtypes and accounts for 26% of all non-cutaneous PTCL’s. These malignancies are derived from mature post thymic T-cells and NK cells. These tumors are uncommon, tend to be aggressive and majority of the patients with T-cell lymphoma present with advanced stage disease and respond poorly to treatment. Relapse rates tend to be high and few patients achieve durable remission with treatment. For these reasons, prognosis remains poor. Agents from two pharmacological classes are presently available for the treatment of PTCL. The FDA granted accelerated approval to FOLOTYN® (Pralatrexate), an antifolate, in 2009, for use in patients with relapsed or refractory PTCL and to ISTODAX® (Romidepsin), a histone deacetylase (HDAC) inhibitor in 2011, for the treatment of PTCL patients, who had received at least one prior therapy.
HDACs are a family of enzymes that play an important role in the regulation of gene expression. To briefly summarize the structure of a chromosome, individual loops of coiled double-helix DNA wrap around a histone protein to form a nucleosome. Nucleosomes are then coiled together to form chromatin fibers, which looks like beads on a string. The chromatin fibers are coiled even more tightly to form chromosomes. HDAC enzymes catalyze the removal of acetyl groups and regulate the level of acetylation of the histones and non-histone proteins and transcription of several genes. Hypoacetylation of histones has been associated with a condensed chromatin structure that results in the repression of gene transcription, whereas acetylated histones are associated with a more open chromatin structure and activation of gene transcription. HDACs are grouped into four major classes and regulate cell-cycle progression, cell survival, angiogenesis and immunity. BELEODAQ® (Belinostat) is a novel pan-histone deacetylase inhibitor and inhibits all 3 classes of the zinc-dependent HDAC enzymes.
The approval of BELEODAQ® was based on the results of a multi-center, single-arm, phase II trial, in which 129 patients with relapsed or refractory PTCL, who had received a median of 2 prior therapies, were enrolled and evaluated. BELEODAQ® was administered as a 30 minute IV infusion at 1000 mg/m2 on days 1–5 of a 3 week cycle until progression or unacceptable toxicity. The median age was 63 years. The primary endpoint was Overall Response Rate (ORR). The ORR was 26% with 10% Complete Responses and 10% Partial responses and the median time to response was 5.6 weeks and the median duration of response was 8.3 months. The most common adverse events were nausea, vomiting, fatigue, fever and anemia. The most common grade 3/4 adverse events were thrombocytopenia (13%), neutropenia (13%), anemia (10%), dyspnea (6%), pneumonia (6%), and fatigue (5%). The authors concluded that BELEODAQ® demonstrated a significant overall response rate in relapsed /refractory PTCL patients, thus expanding the treatment options for these difficult to treat individuals. This was accomplished with a low incidence of myelosuppression and favorable safety profile. O'Connor OA, Masszi T, Savage KJ, et al. J Clin Oncol 31, 2013 (suppl; abstr 8507)
Efficacy and safety of continued zoledronic acid every 4 weeks versus every 12 weeks in women with bone metastases from breast cancer Results of the OPTIMIZE-2 trial
SUMMARY: Bone is the most common site of metastatic disease, in patients with Breast Cancer. Bisphosphonates inhibit osteoclast-mediated bone resorption and both oral and IV bisphosphonates reduce the risk of developing Skeletal Related Events (SRE’s) and delay the time to SRE’s in patients with Breast Cancer with bone metastases. Bisphosphonates can also reduce bone pain and may improve Quality of life. Of the four bisphosphonates proven to be effective in patients with Breast Cancer with bone metastases, only intravenous Pamidronate (AREDIA®) and Zoledronic acid (ZOMETA®) have been approved in the USA, whereas intravenous and oral Ibandronate and oral Clodronate have been approved in Europe. Both AREDIA® and ZOMETA® are administered every 3 to 4 weeks during the first year, following diagnoses of bone metastases. However, the optimal treatment schedule following this initial phase of treatment has remained unclear. Further, renal toxicity, long bone fractures and OsteoNecrosis of the Jaw (ONJ) have been identified as potential problems with bisphosphonate use.
OPTIMIZE-2 is a prospective, randomized, double-blind, multicenter trial, in which the authors evaluated the outcomes of a less intense schedule of ZOMETA® administered every 12 weeks, following one year of the standard initial phase of treatment with bisphosphonates. This study included 403 women with bone metastases from Breast Cancer, who had received 9 or more doses of either intravenous ZOMETA® or AREDIA®, during the first 10-15 months of therapy. The median age was 59 years and patients were randomized (1:1) to receive either ZOMETA® 4 mg IV every 4 weeks (N=200) or every 12 weeks (N=203), for one year. The primary endpoint was Skeletal Related Event (SRE) rate, defined as the proportion of patients with one or more SRE’s (pathologic fractures, spinal cord compression, need for radiotherapy or surgical stabilization of the bone). The primary analysis was non-inferiority, for the difference in SRE rates between the treatment groups. Secondary endpoints included time to first SRE, Skeletal Morbidity Rate (SMR), bone pain score, change in bone turnover markers, and safety. After a median follow up of 11.9 months, the SRE rate was 22% and 23.2% in the ZOMETA® every 4 weeks group and ZOMETA® every 12 weeks group respectively (P=0.724), suggesting that ZOMETA® given every 12 weeks was non-inferior to the q 4 week regimen. The secondary endpoints were comparable as well. More patients had renal toxicities in the ZOMETA® q 4 week group vs q 12 week group (9.6% vs 7.9%, respectively) and two cases (1.0%) of OsteoNecrosis of the Jaw (ONJ) were reported in the ZOMETA® q 4 week group. The authors concluded that the efficacy of continuing ZOMETA® for an additional year at the q 12 week schedule was non-inferior to ZOMETA® given q 4 weeks, among patients who had initially received IV bisphosphonates monthly, for one year or longer. Further the less frequent dosing of ZOMETA® compared with the standard monthly dosing, may be more convenient for the patients and result in less toxicities. Hortobagyi GN, Lipton A, Chew HK, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9500)
Increased Risk of Pancreatic Adenocarcinoma After Acute Pancreatitis
SUMMARY: The American Cancer Society estimates that in 2014, over 46,000 people will be diagnosed with Pancreatic Cancer in the United States and close to 40,000 people will die of the disease. Some important risk factors for Pancreatic Cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease, at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. Early diagnosis may therefore play an important role in treatment outcomes, in patients with Pancreatic Cancer. Pancreatic Cancer can cause acute pancreatitis by obstructing the pancreatic duct and patients diagnosed with Pancreatic Cancer often present initially with acute pancreatitis. With this background information, the authors performed a retrospective study of patients with acute pancreatitis who sought their medical care at the Veterans Health Administration from 1998 through 2007. 
Patients with pre-existing Pancreatic Adenocarcinoma or those with recurrent acute pancreatitis were excluded from this analysis. A diagnosis of acute pancreatitis was made in 5720 patients and 710 patients were diagnosed with Pancreatic Cancer from 2000 through 2007. They noted that of those who were diagnosed with Pancreatic Adenocarcinoma, 76 patients (10.7%) had acute pancreatitis within 2 years of Pancreatic Cancer diagnosis. This risk for Pancreatic Cancer was greatest during the ï¬rst year following diagnosis of acute pancreatitis and this risk decreased rapidly thereafter. Patients less than 40 years of age had negligible risk whereas those 70 years of age or older had the highest risk. The authors concluded that a signiï¬cant number of patients with Pancreatic Adenocarcinoma (12.1%) initially present with acute pancreatitis and the diagnosis of cancer is often delayed by up to 2 years. Acute pancreatitis should be considered as an index event which in turn may identify a population of patients at high risk to develop Pancreatic Adenocarcinoma. They recommend that Endoscopic UltraSound (EUS) should be performed in these high risk patients, following diagnosis of acute pancreatitis, before discharge from the hospital, as this test is highly sensitive in picking up small tumors in the pancreas that are amenable to surgical resection. This is in comparison with contrast enhanced CT scans and pancreatic protocol CT scans that are not as sensitive in identifying tumors less than 2 cm in size. This interesting analysis could potentially open the doors for pancreatic cancer screening in high risk patients. Munigala S, Kanwal F, Xian H, et al. Clinical Gastroenterology and Hepatology 2014;12:1143-1150
Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA) a randomised, open-label, phase 3 trial
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 233,000 new cases of invasive breast cancer will be diagnosed in 2014 and 40,000 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15%-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. It binds to the extracellular domain of the receptor and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). HERCEPTIN® in combination with chemotherapy has been proven to significantly improve Progression Free Survival and Overall Survival in patients with advanced breast cancer. Despite this benefit, majority of these patients develop progressive disease within 18 months. The tumors in these patients continue to express HER2 although the lower sensitivity to HER2 targeted agents has been attributed to HER2 independent escape mechanisms. Treatment strategies for this patient population have included switching chemotherapy in subsequent lines of treatment and continuing HERCEPTIN®, combining another HER2 targeted agent, Lapatinib (TYKERB®) with Capecitabine (XELODA®) and dual HER2 inhibition with a combination of HERCEPTIN® and TYKERB®. KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an antibody-drug conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release.
In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival when compared with TYKERB® and XELODA® in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a taxane. This study however excluded patients who had previously received TYKERB®. TH3RESA is an open label randomized phase III trial in which KADCYLA® was compared with treatment of physician’s choice, in patients with unresectable locally advanced, recurrent or metastatic breast cancer. Eligible patients had a left ventricular ejection fraction of 50% or more, ECOG performance status of 0-2 and had HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting and had progressed on both HERCEPTIN® and TYKERB® containing regimens in metastatic setting and also had disease progression on a taxane, in any setting. Patients were randomized in a 2:1 ratio to receive either KADCYLA® 3•6 mg/kg intravenously every 21 days (N=404) or treatment of physician’s choice (N=198). Treatment was continued until disease progression or unmanageable toxicity. The Co-primary endpoints were Progression Free Survival (PFS) and Overall Survival. Secondary endpoints included Response Rates, duration of response, safety and quality of life. After a median follow up of 7•2 months in the KADCYLA® group and 6•5 months in the physician's treatment choice group, there was a significant improvement in Progression Free Survival with KADCYLA® compared with physician's treatment choice (6•2 months vs 3•3 months, HR= 0•528, P<0•0001). The interim Overall Survival analysis showed a trend favoring KADCYLA® (HR=0•552, P=0•0034). Patients in the KADCYLA® group had a lower incidence of grade 3 toxicities compared to the patients in the physician’s treatment choice group (32% vs 43%). Grade 3 thrombocytopenia however was more common in the KADCYLA® group compared to the physician’s choice group (5% vs 2%) and this has been attributed to the inhibition of megakaryocyte differentiation by KADCYLA®. The authors concluded that KADCYLA® should be considered the treatment of choice, for patients with HER2-positive advanced breast cancer, who have previously received HERCEPTIN® and TYKERB®. It remains to be seen however, if KADCYLA® is effective in patients who had progressed on Pertuzumab (PERJETA®) based therapies. Krop IE, Kim SB, González-Martín A, et al. Lancet Oncol. 2014;15:689-699
Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL)
SUMMARY: It is estimated that in the US, approximately 76,000 new cases of melanoma will be diagnosed and close to 8000 individuals will die of the disease in 2014. The incidence of melanoma has been on the rise for the past three decades. Unlike other malignancies, the role of chemotherapy for the treatment of melanoma has been limited. Treatment of advanced melanoma with immunotherapy using a cytokine, Interleukin-2 (IL-2) produced by T cells during an immune response, was first explored in the mid 1970’s. Durable responses were noted in a very small percentage of patients but this was associated with significant toxicities. This however opened the doors for the development of various immunotherapies, with a better understanding of the Immune checkpoints. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response, by switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or Gate Keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1 (Programmed cell Death-1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. The first immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® (Ipilimumab), an antibody that blocks Immune checkpoint protein/receptor CTLA- 4, has been shown to prolong overall survival in patients with previously treated, unresectable or metastatic melanoma.
The Food and Drug Administration in May 2014, granted Pembrolizumab a Priority Review designation under its Accelerated Approval Program. Pembrolizumab was previously granted a Breakthrough Therapy designation for advanced melanoma. The authors in this largest phase I clinical trial ever done in patients with malignant melanoma, evaluated the efficacy and safety of Pembrolizumab (formerly known as MK-3475, Lambrolizumab), a humanized monoclonal IgG4 anti PD-1 antibody, in a pooled analysis of 411 patients with advanced melanoma. Of these patients, 221 patients had prior therapy with Ipilimumab (YERVOY® ) and 190 patients were YERVOY® naïve. In this study, three different dosing schedules for Pembrolizumab were utilized – 2 mg/kg every three weeks (N=162), 10 mg/kg every three weeks (N=192) and 10 mg/kg every two weeks (N=57). At the time of this analysis, all patients had at least 6 months of follow up and 75% of the patients had been followed up for at least 9 months. The Overall Response Rate was 40% in the YERVOY® naïve group and 28% in the YERVOY® treated group. Responses were durable and ongoing (88% ongoing) at the time of this analysis. The duration of responses ranged from 6 to 76 weeks, and the median response duration has not yet been reached. The median Progression Free Survival was 24 weeks in YERVOY® naïve group and 23 weeks in the YERVOY® treated group. The median Overall Survival has not been reached at the time of this analysis and the estimated 1 year Overall Survival rate for all patients was 71%. The activity with Pembrolizumab was demonstrated across all dose levels and patient subgroups, irrespective of prior YERVOY® therapy, performance status, LDH levels, BRAF mutation status, tumor stage, and number, as well as type of prior therapies. The most common adverse events of any grade were fatigue, pruritus and rash. Only 4% of the patients discontinued treatment due to a drug related toxicities and overall, 12% of patients experienced grade 3/4 adverse events. The authors concluded that the PD-1 targeting antibody, Pembrolizumab, produced durable responses in patients with advanced melanoma, regardless of prior therapy with YERVOY® and this benefit was accomplished with minimal toxicities. This efficacy data is comparable to another PD-1 targeted monoclonal antibody, Nivolumab. Because of the lack of cross resistance between anti PD-1 antibodies and YERVOY®, combining PD-1 targeted monoclonal antibody with a CTLA-4 targeted antibody such as YERVOY®, could potentially be synergistic, with better outcomes. Ribas A, Hodi FS, Kefford R, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA 9000)</s
Long-term treatment with testosterone undecanoate injections and its effect of prostate cancer incidence in hypogonadal men
SUMMARY: Aging Male Syndrome (AMS), also known as late-onset hypogonadism is a common condition associated with low testosterone levels and symptoms and signs of hypogonadism. They include weight gain, insomnia, irritability and mood swings, fatigue, loss of libido, loss of motivation, problems with memory and concentration, bone loss, loss of muscle mass and anemia. There is ample evidence suggesting that testosterone replacement therapy improves quality of life in men with Aging Male Syndrome. A definite correlation has not been established, between adjusted testosterone levels in hypogonadal men using testosterone replacement therapy and the initiation and/or promotion of latent prostate cancer.
Based on the recent research, it appears that there is an indirect link between mutations of the Androgen Receptor gene and the initiation and promotion of prostate cancer. On the contrary, low testosterone levels prior to therapy may be an independent predictor of a more aggressive disease, with an increased likelihood of extra-prostatic disease at the time of diagnosis and unfavorable treatment response. The current recommendations are to exclude prostate cancer before initiating testosterone replacement therapy in hypogonadal men over age 40, with a digital rectal examination (DRE) and PSA level and to closely monitor in the first year of testosterone replacement with DRE and PSA evaluations every 3 months and then semiannually. These recommendations are arbitrary, and not supported by published data. To determine the incidence/risk of prostate cancer with testosterone replacement therapy, the authors in this study reviewed the outcomes of 942 men in three cohorts, with testosterone levels less than or equal to 12.1 nmol/L from three German centers, who had received testosterone undecanoate for up to 16 years. The incidence of prostate cancer in cohort A (N=300) was 39.4 per 10,000 person-years (39.4 cases per 10,000 persons followed for 1 year), in cohort B (N=261) was 54.5 per 10,000 person-years (54.5 cases per 10,000 persons followed for 1 year) and in cohort C (N=381), no person was diagnosed with prostate cancer. The authors pointed out that the incidence of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was 116 per 10,000 person-years. Even though this review of registry data cannot be directly compared with screening trials, the authors concluded that based on their registry studies, long-term testosterone treatment in hypogonadal men does not appear to increase prostate cancer risk. A recently published article, in the Annals of Pharmacotherapy by Baillargeon, et al. concluded that there was no increased risk of myocardial infarction when hypogonadal patients over age 65, were treated with intramuscular testosterone. As the debate continues on the risk/ benefits of testosterone replacement therapy, the heightened awareness will probably bring about more responsible prescribing of testosterone supplements. Haider A, Zitzmann M, Yassin A. J Clin Oncol 32, 2014 (suppl 4; abstr 119)
Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma Results from the phase III RESONATE trial
SUMMARY: The American Cancer Society estimates that approximately 15,720 new cases of chronic lymphocytic leukemia (CLL) will be diagnosed in 2014 and approximately 4600 patients will die from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. There are two main types of lymphocytes, B and T lymphocytes/cells, and B-cell CLL is the most common type of leukemia in adults. 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, and NF-κB pathways and resulting B-cell activation and proliferation. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis). The 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 (SLL). In this study, 391 patients who had measurable nodal disease and received at least one prior therapy, were randomized to receive 420 mg of IMBRUVICA® orally once daily until progression (N=195) or ARZERRA® at an initial dose of 300 mg followed by 11 doses at 2000 mg, given intravenously weekly (N=196). Patients randomized to the ARZERRA® group, on disease progression were allowed to receive treatment with IMBRUVICA®. The median age was 67 years, 40% of the patients enrolled in the study were 70 years of age or over and 30% of patients had deletion of chromosome 17p. The primary endpoint of this study was Progression-Free Survival (PFS) and the secondary endpoints included Overall Survival (OS), Overall Response rate (ORR) and safety. 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 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. The Overall Response Rates were significantly higher in the IMBRUVICA® group compared to the ARZERRA® group (42.6% vs 4.1% (P <0 .0001). An additional 20% of patients treated with IMBRUVICA® had a partial response of their persistent lymphocytosis. The benefit with IMBRUVICA® was similarly high even in the two very high risk groups of patients such as those with 17p deletions and those refractory to purine analog chemoimmunotherapy. The overall survival was significant despite the crossover of 57 patients upon progression, from the ARZERRA® group to IMBRUVICA®. Treatment was well tolerated in both groups. Diarrhea, fatigue, nausea and atrial fibrillation were more frequent in the IMBRUVICA® group but did not result in frequent dose reductions or treatment discontinuation. The authors concluded that IMBRUVICA® significantly improved Progression Free Survival, Overall Survival and Overall Response Rates, in patients with relapsed/refractory CLL/SLL, compared with ARZERRA® and IMBRUVICA® should also be a consideration for elderly patients who often are unable to tolerate intensive chemotherapy. Byrd JC, Brown JR, O’Brien SM, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA7008)
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Of The Efficacy and Safety Of Siltuximab, An Anti-Interleukin-6 Monoclonal Antibody, In Patients With Multicentric Castleman’s Disease
SUMMARY: Castleman Disease (CD) also known as giant lymph node hyperplasia and angiofollicular lymph node hyperplasia is a disease of lymph nodes and related tissues and can be Unicentric (localized) or Multicentric. Younger individuals are more likely to have the localized form whereas older adults and those with HIV infection are more likely to have the Multicentric form. Unicentric CD only affects a single group of lymph nodes and curative resection of the affected lymph nodes is feasible. Multicentric Castleman Disease (MCD) behaves like a lymphoma and is classified as a lymphoproliferative disorder and requires treatment intervention. The number of people diagnosed with MCD has been increasing with the rising incidence of HIV infection. Even though retroviral therapies have improved survival in patients with HIV infection, this has not impacted the incidence of MCD. Approximately 50% of the MCD cases have been attributed to Kaposi's Sarcoma-associated Herpes Virus (KSHV), also known as HHV-8, a gamma herpes virus which is a causative factor for Kaposi's sarcoma and Primary Effusion Lymphoma, while the cause of the remainder of the MCD cases is unknown.
There are three microscopic subtypes of CD – The hyaline vascular type which is localized (Unicentric) type, the plasma cell type which is more likely to be Multicentric, and the mixed subtype which occurs less often. The microscopic findings are less important when it comes to treatment whereas treatment is based on whether the disease is Unicentric or Multicentric. KSHV is closely associated with plasmacytic form of MCD while the hyaline vascular type is generally negative for KSHV. Patients with Multicentric CD usually experience fevers, night sweats, weight loss, fatigue as well as leukocytopenia, hypergammaglobulinemia, generalized lymphadenopathy and possible splenic involvement. It resembles angioimmunoblastic lymphadenopathy and the symptoms and signs have been attributed to dysregulated interleukin (IL)-6 production. Some patients with CD may have normal IL-6 levels and present with microcytic anemia without iron deficiency, which resolves after effective therapy. MCD is seen in patients with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes) and has been implicated in 10% of cases of paraneoplastic pemphigus. Based on the preliminary data demonstrating the efficacy of SYLVANT® (Siltuximab), a chimeric monoclonal antibody targeting human IL-6, in MCD patients, an international, multicenter, randomized phase II trial was conducted. Patients with Multicentric Castleman Disease (MCD) who were Human Immunodeficiency Virus (HIV) negative and Human Herpes Virus-8 (HHV-8) negative (N=79) were randomized 2:1 to receive SYLVANT® (Siltuximab) given every three weeks, as an IV infusion at a dose of 11 mg/kg along with Best Supportive Care (N=53) or Placebo plus Best Supportive Care (N=26). The median age was 48 yrs, 30% were on corticosteroids and 58% had prior systemic therapy. Primary endpoint was durable tumor and symptomatic response defined as PR or CR by independent review and improvement or stabilization in MCD-related symptoms for 18 weeks or more. Secondary endpoints included additional predefined efficacy measures and safety. The durable tumor and symptomatic response rates (Primary endpoint) were 34% versus 0% for the SYLVANT® and Placebo groups respectively (P=0.0012). With regards to secondary endpoints, tumor response rates were 38% versus 4% for the SYLVANT® and placebo groups, respectively (P<0.05), the median time to treatment failure was 134 days in those receiving placebo and had not been reached in the SYLVANT® (P=0.0084), an increase in the hemoglobin of at least 1.5 grams/dL at week13 in anemic patients was seen in 61% of the patients receiving SYLVANT® vs 0% in those receiving Placebo (P=0.0002). There were sustained decreases in C-Reactive Protein (a marker of IL-6 activity), ESR, and fibrinogen as well as an increase in albumin in the SYLVANT® group. The common adverse reactions (>10% compared to placebo) during treatment with SYLVANT® were pruritus, weight gain, rash, hyperuricemia and upper respiratory tract infections. The authors concluded that this is the first randomized study involving patients with Multicentric Castleman Disease, that has demonstrated significant efficacy with SYLVANT®, resulting in durable tumor and symptom responses and added clinical benefit. Wong RS, Casper C, Munshi N, et al. Abstract #505. ASH Annual Meeting and Exposition, 2013