Tag: General Medical Oncology & Hematology

SUMMARY: The FDA on May 24, 2019 approved JAKAFI® (Ruxolitinib) for steroid-refractory acute Graft-Versus-Host Disease (GVHD) in adult and pediatric patients 12 years and older. Acute GVHD is a frequent and severe inflammatory complication of allogeneic Hematopoietic Cell Transplantation (HCT), and is a reaction of donor immune cells against host tissues. It is estimated that in the US over 8000 patients undergo allogeneic HCT each year and about 35-50% of recipients will develop acute GVHD, which remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Following the preparative regimen, a series of inflammatory reactions lead to damage to the host epithelial cells by activated donor T cells. GVHD can be acute or chronic, with acute GVHD typically occurring within the first 100 days following an allogeneic transplant. Approximately 40% of patients with acute GVHD have severe disease, with a one year survival of 50% or less. Acute GVHD typically involves the skin, often starting in the palms and soles (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). Acute GVHD is a clinical diagnosis, although histologic confirmation may be extremely helpful, if the symptoms and presentation are atypical. Risk factors for the development of acute GVHD include degree of HLA disparity, gender disparity, increased age of both the recipient and the donor, multiparous female donors, ineffective GVHD prophylaxis, intensity of the transplant conditioning regimen and the source of graft (peripheral blood or bone marrow greater than umbilical cord blood).

Patients with acute GVHD are often treated by optimizing their immunosuppression and adding methylprednisolone, with approximately 50% of patients responding to this intervention. If symptoms do not improve after a week or if progression is noted after 3 days of treatment, patients receive salvage immunosuppressive intervention, since no standard treatment with meaningful benefit has been identified.

JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor and exerts its mechanism of action by targeting and inhibiting the dysregulated JAK2-STAT signaling pathway. JAKAFI® in animal models was shown to reduce IL-1β, IL-6, or IFN-γ and TNF and other cytokines implicated in lymphocyte activation characteristic of GVHD. In previously published studies, JAKAFI® when used in patients with refractory GVHD demonstrated an Overall Response Rate of 85% in acute or chronic GVHD, with a 25% Complete Remission rate.

The present FDA approval was based on data from REACH1 study, which is an open-label, single-arm, multicenter, phase II trial of JAKAFI® in combination with corticosteroids, in patients with steroid-refractory grade II-IV acute GVHD. Of the 71 patients enrolled in this study, 49 patients were refractory to steroids alone, 12 patients had received two or more prior therapies for GVHD and 10 patients did not otherwise meet the FDA definition of steroid-refractory state. JAKAFI® was administered at 5 mg orally twice daily, and the dose could be increased to 10 mg twice daily after three days, in the absence of toxicity.

The Primary endpoint of this trial was the Day 28 Overall Response Rate (ORR), defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR), based on the Center for International Blood and Marrow Transplant Research (CIBMTR) criteria. The Day 28 ORR in the 49 patient’s refractory to steroids alone was 57% with a CR rate of 31%. The most frequently reported adverse reactions were infections (55%) and edema (51%), and the most common laboratory abnormalities were anemia, thrombocytopenia and neutropenia.

It was concluded that for patients with acute GVHD who do not adequately respond to steroids, therapies are limited and JAKAFI® is a new treatment option that fulfills this unmet need. Results from REACH1, a Single-Arm Phase 2 Study of Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease. Jagasia M, Perales M-A, Schroeder MA, et al. Blood 2018 132:601; doi: https://doi.org/10.1182/blood-2018-99-116342

SUMMARY: Patients undergoing cytotoxic chemotherapy and Hematopoietic Stem Cell Transplantation (HSCT), when neutropenic, are at risk for infection. The risk of infection increases with the depth and duration of neutropenia. The greatest infection risk is among those who experience profound, prolonged neutropenia after chemotherapy. Neutropenia is defined as an absolute neutrophil count of less than 1,000/µL, severe neutropenia as absolute neutrophil count less than 500/µL and profound neutropenia as less than 100/µL. Neutropenia is considered protracted if it lasts for 7 days or more. Fever in neutropenic patients is defined as a single oral temperature of 38.3°C (101°F) or more or a sustained temperature of 38.0°C (100.4°F) or more over a period of 1 hour.

The ASCO in partnership with Infectious Diseases Society of America (IDSA) convened an Expert Panel and updated the 2013 ASCO guideline on antimicrobial prophylaxis for immunosuppressed adult patients undergoing treatment of malignancy. The expert panel conducted a systematic review of relevant studies which included six new or updated meta-analyses and six new primary studies, from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel.

KEY RECOMMENDATIONS

CLINICAL QUESTION 1 – Antibacterial Prophylaxis: Does antibacterial prophylaxis with a Fluoroquinolone, compared with placebo, no intervention, or another class of antibiotic, reduce the incidence of and mortality as a result of febrile episodes in patients with cancer?

Recommendation: Antibiotic prophylaxis with a Fluoroquinolone is recommended for patients who are at high risk for Febrile Neutropenia or profound, protracted neutropenia, such as those patients with Acute Myeloid Leukemia/Myelodysplastic syndromes (AML/MDS) or Hematopoietic Stem Cell Transplantation (HSCT) treated with myeloablative conditioning regimens. Antibiotic prophylaxis is not routinely recommended for patients with solid tumors, for patients who are at low risk of profound, protracted neutropenia and when CSF prophylaxis effectively reduces the severity and duration of neutropenia.

CLINICAL QUESTION 2 – Antifungal Prophylaxis: Does antifungal prophylaxis with an oral triazole or parenteral Echinocandin, compared with no prophylaxis, or another treatment option, reduce the incidence of and mortality, as a result of febrile episodes in patients with cancer?

Recommendation 2.1: Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients who are at risk for profound, protracted neutropenia and mucositis, such as most patients with AML/MDS or HSCT. Antifungal prophylaxis is not routinely recommended for patients with solid tumors. Clinicians should be able to differentiate the risks for invasive candidiasis from the risks for invasive mold infection. This is because Fluconazole is active against yeast but not mold whereas Echinocandins and other azole antifungals, such as Posaconozole, Voriconozole, or Isavuconazole are mold-active agents. A mold-active triazole is recommended where the risk of invasive Aspergillosis is more than 6%, such as in patients with AML/MDS during the neutropenic period associated with chemotherapy, in the late stage postallogeneic SCT and/or in the context of GVHD. Antifungal prophylaxis is not routinely recommended for patients who are at low risk of profound, protracted neutropenia and when CSF prophylaxis effectively reduces the severity and duration of neutropenia.

Recommendation 2.2: Prophylaxis is recommended with Trimethoprim-Sulfamethoxazole (TMP-SMX), for patients receiving chemotherapy regimens associated with more than 3.5% risk for pneumonia from Pneumocystis jirovecii (eg, for those on 20 mg or more of prednisone daily for more than 4 weeks). For those hypersensitive to Sulfonamides or unable to tolerate TMP-SMX, alternative options include Dapsone, aerosolized Pentamidine, or Atovaquone.

CLINICAL QUESTION 3 – Antiviral Prophylaxis: Does antiviral prophylaxis reduce the incidence of immunosuppression-related viral infections in patients with cancer compared with no prophylaxis or another treatment option?

Recommendation 3.1: Herpes Simplex Virus-seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis with a nucleoside analog such as Acyclovir.

Recommendation 3.2: For patients who are at high risk of Hepatitis B Virus reactivation, treatment with a nucleoside reverse transcription inhibitor (eg, Entecavir or Tenofovir) is recommended.

Recommendation 3.3: Yearly influenza vaccination with inactivated quadrivalent vaccine is recommended for all patients receiving chemotherapy for malignancy and all family and household contacts and health care providers. It is best administered more than 1 week after the last treatment or more than 2 weeks before chemotherapy administration. Individuals older than 65 years should receive the high-dose vaccine.

Recommendation 3.4: The Expert Panel also supports other vaccination recommendations for immunosuppressed adult oncology patients that are contained within the IDSA guideline for vaccination of the immunosuppressed patients.

CLINICAL QUESTION 4 – Do additional precautions, such as hand hygiene, air filtration, or a neutropenic diet, reduce the risk of infection in neutropenic patients with cancer compared with no or other additional precautions?

Recommendation 4.1: All health care workers should comply with hand hygiene and respiratory hygiene/cough etiquette guidelines to reduce the risk for aerosol- and direct or indirect contact-based transmission of pathogenic microorganisms in the health care setting.

Recommendation 4.2: Outpatients with neutropenia from cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores (eg, construction and demolition sites, intensive exposure to soil through gardening or digging, or household renovation).

Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. Taplitz RA, Kennedy EB, Bow EJ, et al. J Clin Oncol 2018;36:3043-3054

SUMMARY: The FDA on November 26, 2018, granted accelerated approval to VITRAKVI® (Larotrectinib) for adult and pediatric patients with solid tumors that have a NeuroTrophic Receptor tyrosine Kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. This is the second tissue-agnostic FDA approval for the treatment of cancer. Tumor genomic profiling enables the identification of specific genomic alterations and thereby can provide personalized treatment options with targeted therapies that are specific for those molecular targets. The FDA in May 2017 granted accelerated approval to KEYTRUDA® (Pembrolizumab), for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) solid tumors. This was the first FDA approval of a systemic cancer treatment, based on a specific genetic biomarker, independent of tumor origin (first tissue/site-agnostic approval).

A genomic test can be performed on a tumor specimen or on cell-free DNA in plasma (“liquid biopsy”). ImmunoHistoChemistry (IHC) test can be performed on tumor tissue for protein expression that demonstrates a genomic variant known to be a drug target, or to predict sensitivity to a chemotherapeutic drug. Next-generation sequencing (NGS) platforms or second-generation sequencing unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. Recently reported genomic profiling studies performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors. Next-generation sequencing has enabled the detection of Neurotrophic Tropomyosin Receptor Kinase (NTRK) gene fusions, which was first discovered in colon cancer in 1982. The three TRK family of Tropomyosin Receptor Kinase (TRK) transmembrane proteins TRKA, TRKB, and TRKC are encoded by Neurotrophic Tropomyosin Receptor Kinase genes NTRK1, NTRK2, and NTRK3, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and are involved in a variety of signaling events such as cell differentiation, cell survival and apoptosis of peripheral and central neurons. They therefore play an essential role in the physiology of development and function of the nervous system. There are over 50 different partner genes that fuse with NTRK genes. Chromosomal fusion involving NTRK genes arise early in cancer development and remain so as tumors grow and metastasize. Gene fusions involving NTRK genes lead to transcription of chimeric TRK proteins which can confer oncogenic potential by increasing cell proliferation and survival. Early clinical evidence suggests that these gene fusions lead to oncogene addiction regardless of tissue of origin. (Oncogene addiction is the dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype). It is estimated that gene fusions involving NTRK genes occurs in about 0.5% to 1% of many common malignancies but in more than 90% of certain rare tumor types, such as salivary gland tumors, a form of juvenile breast cancer, and infantile fibrosarcoma.

The approval of VITRAKVI®, a potent and highly selective, oral, small molecule inhibitor of all three TRK proteins was based on data from three multicenter, open-label, single-arm clinical trials – LOXO-TRK-14001, a phase I study involving adults, SCOUT, a phase I-II study involving children and NAVIGATE, a phase II study involving adolescents and adults. The authors in this development program included patients of any age and with any tumor type who had chromosomal fusion involving NTRK genes (Age and Tumor agnostic therapy). Positive NTRK gene fusion status was prospectively determined in local laboratories using NGS or Fluorescence In Situ Hybridization (FISH). Treatment efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the three trials. All patients were required to have progressed following systemic therapy for their disease if available, or would have required surgery with significant morbidity for locally advanced disease. Twelve patients were less than 18 years of age. A total of 12 cancer types were represented, with the most common being salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%). NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The Primary end point for the combined analysis was the Overall Response Rate (ORR) according to Independent review. Secondary end points included Duration of Response, Progression Free Survival, and safety.

The ORR was 75%, including 22% Complete Responses and 53% Partial Responses. At the time of database lock, median Duration of Response had not been reached. Response duration was 6 months or longer for 73%, 9 months or longer for 63%, and 12 months or longer for 39% of patients. The safety of VITRAKVI® was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions (20% or more) with VITRAKVI® were fatigue, nausea, vomiting and abnormal liver function studies. None of the patients on VITRAKVI® discontinued therapy, due to a drug-related adverse event.

It was concluded that TRK fusions defined a unique molecular subgroup of advanced solid tumors in children and adults and VITRAKVI® had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of age of the patient or tumor type. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. Drilon A, Laetsch TW, Kummar S, et al. N Engl J Med 2018; 378:731-739

SUMMARY: Cancer along with Cardiovascular disease, Diabetes, Chronic Kidney Disease and Respiratory disease, account for over 80% of all chronic disease deaths. Gouty arthritis is the most common inflammatory arthritis worldwide. Chronic inflammation may be the common denominator for chronic diseases and cancer, although other mechanisms may come into play. Patients with chronic diseases have associated lifestyle risk factors as well, which can reduce life span and increased cancer risk.

The purpose of this Prospective cohort study was to assess the independent as well as joint associations of several common chronic diseases and disease markers with cancer risk, and to explore the benefit of physical activity in reducing the cancer risk associated with chronic diseases and disease markers.

This study cohort consisted of 405,878 participants and the authors selected five common chronic diseases for evaluation, which account for most of the disease burden worldwide. They included Cardiovascular disease and associated markers such as diastolic blood pressure and systolic blood pressure, total cholesterol level, and heart rate, Diabetes and fasting blood glucose level using WHO criteria, Chronic Kidney Disease markers such as dipstick proteinuria and estimated Glomerular Filtration Rate using National Kidney Foundation criteria, Pulmonary disease markers such as Forced Expiratory Volume in one second and Forced Vital Capacity using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria and Gouty arthritis marker such as uric acid. In this study, 48% were men and 52% were women. These participants were followed for an average of 8.7 years and the main outcome measures were cancer incidence and cancer mortality overall, as well as cancer specific incidence and mortality. The eight chronic diseases or markers included Blood Pressure, Total Cholesterol, Heart Rate, Diabetes, Proteinuria, Glomerular Filtration Rate, Pulmonary disease and Gouty arthritis marker Uric acid.

The authors observed a statistically significantly increased risk of incident cancer for the eight diseases and markers individually with the exception of Blood Pressure and Pulmonary disease. All eight diseases and markers were statistically significantly associated with risk of cancer death. Population Attributable Fraction (PAF) is the proportional reduction in population disease or mortality that would occur if exposure to a risk factor were reduced to an alternative ideal exposure scenario (eg. no tobacco use). The PAFs of cancer incidence or cancer mortality from the eight chronic diseases and markers together were comparable to those from five major lifestyle factors – ever smoking, insufficient physical activity, insufficient fruit and vegetable intake, ever alcohol consumption, and non-ideal BMI, combined (cancer incidence: 20.5% versus 24.8%; cancer mortality: 38.9% versus 39.7%). Among physically active (versus inactive) participants, the increased cancer risk associated with chronic diseases and markers was decreased by 48% for cancer incidence and 27% for cancer mortality.

It was concluded that chronic diseases contribute to more than 20% of the risk for incident cancer and more than one third of the risk for cancer death and is as important as five major lifestyle factors combined. Physical activity is associated with significant reduction in the cancer risk associated with chronic diseases. Cancer risk associated with chronic diseases and disease markers: prospective cohort study. Tu H, Wen CP, Tsai SP, et al. BMJ 2018;360:k134