CYRAMZA® (Ramucirumab)

The FDA on December 12, 2014 approved CYRAMZA® for use in combination with TAXOTERE® (Docetaxel) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA®. CYRAMZA® injection for intravenous infusion is a product of Eli Lilly and Company.

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

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

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

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

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

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

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

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

A phase 3 randomized, open-label study of nivolumab (anti-PD-1;BMS-936558; ONO-4538) versus investigator's choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy

SUMMARY: The FDA on December 22, 2014 granted accelerated approval to OPDIVO® (Nivolumab) for the treatment of patients with unresectable or metastatic melanoma whose disease has progressed following YERVOY® (Ipilimumab) and if BRAF V600 mutation positive, a BRAF inhibitor. 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 a novel immunotherapeutic approaches, with a better understanding of the Immune checkpoints. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They 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 therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and 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. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® in previously conducted studies demonstrated durable antitumor activity and promising overall survival (OS) in pretreated patients. CheckMate-037 is an open label, randomized, phase III study, in which 370 patients with unresectable or metastatic melanoma, received OPDIVO® 3 mg/kg IV every 2 weeks (N=268) or investigator’s choice of chemotherapy, which included either Dacarbazine or a combination of Carboplatin plus Paclitaxel given every 3 weeks (N=102). Treatment was continued until disease progression or unacceptable toxicity. Eligible patients were required to have disease progression following YERVOY® (Ipilimumab) and a BRAF inhibitor if BRAF V600 mutation positive. The primary endpoints were ORR and overall survival. Early findings (Objective Response Rate-ORR) in the first 120 patients who were treated with OPDIVO® and in 47 patients treated with chemotherapy and had a minimum 6 months follow up (planned interim analysis), was presented at the 2014 ESMO Congress. The Objective Response Rate (ORR) was 32% in the OPDIVO® group and 11% in the chemotherapy group. The median time to response was 2.1 months in the OPDIVO® group and 3.5 months with chemotherapy. The majority, (95%) of responses at 6 months were ongoing in the OPDIVO® group and the median duration of response was not reached. The most common (greater than or equal to 20%) adverse reaction in the OPDIVO® group was rash. Grade 3 and 4 adverse events were seen in 2-5% of patients receiving OPDIVO® and included abdominal pain, hyponatremia, elevated liver enzymes and increased lipase. Clinically significant immune-mediated adverse reactions were pneumonitis, colitis, hepatitis, nephritis, and thyroid dysfunction. OPDIVO® is a new and novel treatment option for patients with advanced melanoma and is a welcome addition, as we try to better understand tumor immunology. Weber JS, Minor DR, D'Angelo S, et al. ESMO 2014, LBA3_PR