Optimizing CAR T-cell therapies in lymphoma: Improving response, fighting cytokine release syndrome, and identifying mechanisms of resistance

Existing biosimilars are safe, effective alternatives to their reference biologics, and are increasingly being incorporated into oncology treatment guidelines. Technological advances that have emerged in the years since biologic agents entered the market allow for the careful assessment of “critical clinical attributes” of biosimilar agents. This helps ensure the safety and efficacy of biosimilars, as well as their structural, functional, and behavioral similarities to the original reference biologics, according to Gary Lyman MD, MPH, professor and senior lead, health care quality and policy at the Hutchinson Institute for Cancer Outcomes Research at Fred Hutchinson Cancer Research Center, Seattle. Biosimilars are increasingly being included as acceptable alternatives in treatment guidelines, and in this episode Dr. Lyman discussed the reasons why they are considered safe and effective, how they can add value for oncology patients, and the need for ongoing diligence in monitoring their effects. Biosimilars in oncology – key points: The developers of biosimilar agents must prove biosimilarity to the reference agent, and generally go through “many of the same, if not all, preclinical steps.” Regulatory requirements are sufficient to ensure there are no clinically meaningful differences in the safety, purity, strength, and efficacy of biosimilars. Unlike the originator biologics, biosimilars aren’t typically required to complete multiple costly phase 3 clinical studies that drive up drug costs. This has the potential to rein in drug prices for biologics, which have revolutionized oncology and many other fields – but at a significant price. There has been some progress with respect to biologic cost reductions in the wake of biosimilar approvals, but the cost effects of biosimilars for newer reference agents will take time to emerge. Further prolonging the cost-reducing effects of biosimilar availability is the fact that early biosimilars were mainly used for supportive care whereas newer biosimilars are more often used for curative intent, which may lead to slower uptake due to hesitancy among clinicians and patients. The European Medicines Agency (EMA) is about a decade ahead of the United States when it comes to approvals and acceptance of biosimilars. Of note, no approved biosimilar has been removed from the market due to concerns about safety and efficacy. This is “a huge testament to the durability of biosimilars and the strength of the regulatory process,” Dr. Lyman said, noting that the EMA and FDA have similar processes when it comes to such approvals. “Drift,” the inevitable changes over time in an agent’s characteristics, can lead to changes in safety and efficacy. This means that diligence in monitoring effects and outcomes with both biologics and biosimilars is essential. Any concerns should be reported immediately and investigated. Show notes written by Sharon Worcester, MA, a reporter for MDedge and Medscape. Disclosures Dr. Henry has no relevant disclosures. Dr. Lyman disclosed relationships with Amgen, Jazz Pharmaceuticals, Partners Therapeutics, Sandoz, Seattle Genetics, Bristol Myers Squibb, BeyondSpring, Samsung, G1 Therapeutics, and Merck. * * * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

Systemic treatment for advanced urothelial cancer is quickly evolving. On this week’s podcast, Arjun Balar, MD, director of the genitourinary medical oncology program at New York University discusses his approach amid changing times with guest host Alan Lyss, MD, a community-based medical oncologist and clinical researcher in the St. Louis area before his recent retirement.  Chemotherapy or immunotherapy first line? With the negative phase 3 results for chemotherapy in combination with either pembrolizumab or atezolizumab, “if I use immunotherapy, I use it alone,” Dr. Balar said. Patients who need “a response right away” for aggressive disease get chemotherapy. In general, first-line chemotherapy “probably is the better route for a lot of people,” he said. There is a role for immunotherapy in the first line when chemotherapy can’t be tolerated because of age or other reasons, and in the second line, immunotherapy is standard of care. PD-1/PD-LI expression is too inconsistent to help guide the decision. It’s based instead on clinical judgement, given patient and disease characteristics. Antibody-drug conjugates The class includes enfortumab vedotin and sacituzumab govitecan, both approved for third-line treatment after chemo and immunotherapy. Essentially, they are homing molecules targeting cancer-specific antigens coupled with a potent cytotoxic payload. They have strong potential in combination with immunotherapy. “I think, in the next 3-5 years, we're going to find ADCs plus immunotherapy become the new standard of care,” Dr. Balar said. New enfortumab vedotin data show activity in the second line among medically frail patients ineligible for chemotherapy who were treated instead with immunotherapy for metastatic disease. “This drug can potentially rescue those patients as an option after immunotherapy,” said Dr. Balar, an enfortumab vedotin investigator. Next-generation sequencing There’s no role yet for sequencing in the first line, but it’s necessary in later lines to check eligibility for drugs aimed at specific mutations, such as the tyrosine kinase inhibitor erdafitinib for patients with susceptible FGFR3 or FGFR2 genetic alterations. Assays are available commercially from Foundation and other companies. Results can take up to 6 weeks, so “I do it early on. I know that information is potentially going to be useful in making treatment decisions,” Dr. Balar said. Enfortumabe vedotin adverse events Side effects can include hyperglycemia within the first one or two cycles. Sometimes it’s asymptomatic, sometimes it’s accompanied by acid-base disturbances, and in very rare cases, it’s fatal. The problem is possibly linked to higher baseline body mass index. At least half of patients develop a sunburn-like rash, also within the first one or two cycles, that spares the face and can be pruritic. It’s manageable by topical steroids, oral antihistamines, dose reductions, or dose interruptions. “If anything severe is going to happen, it's going to happen within the first one or two cycles. I see [patients at] every visit” in the first two cycles “primarily to catch anything untoward,” Dr. Balar said. Neuropathy is the “most significant dose-limiting toxicity, and tends to develop about 4 months into treatment,” he said. Show notes written by M. Alexander Otto. Dr. Balar disclosed research, advisory, and/or speaker relationships with Genentech, Incyte, Bristol-Myers Squibb, Janssen, Merck, Pfizer, AstraZeneca, and other companies. Dr. Lyss writes a column for MDedge Hematology/Oncology called “Clinical Insights” and had no other conflicts of interest.

A “very basic” type of gene therapy could potentially cure hemophilia, but a major hurdle has been the lack of an effective mode of delivery. Recent strides in using adeno-associated virus (AAV) vectors are changing that, and Glenn Pierce, MD, World Federation of Hemophilia Vice President, Medical, predicts approvals in the next 12-18 months. Dr. Pierce shared his personal experience with hemophilia and discussed his and others’ ongoing research on the use of AAV-mediated gene therapy with host David Henry, MD, in this episode. Hemophilia and AAV gene therapy key points: Hemophilia is caused by a monogenic defect and could, theoretically, be cured by gene replacement or augmentation, says Dr. Pierce, who notes that “it sounds disarmingly simple, but behind that simplicity is a very complex procedure.” The approach uses “gene addition,” which is a basic gene therapy involving the addition of a normal gene to the variant in an individual. This ultimately corrects the clotting factor deficiency. The complexity is in getting the normal gene into the body where it can have the intended therapeutic effect. After more than 20 years of working to overcome that barrier, Dr. Pierce and others are finding success with using AAVs. The approach has some similarities to that used in developing the mRNA COVID-19 vaccines but requires the use of DNA established within the virus (rather than mRNA) to provide a more stable effect. Questions about how long it will last are currently being investigated. Multiple phase 3 trials are underway or completed. Data from two of those have been released in recent months, and the results are very encouraging: “It’s a remarkable achievement – many patients are doing well and, for all intents and purposes, could be considered free of [hemophilia],” Dr. Pierce says, adding that he would “potentially … use the ‘C word’ – cured – for at least a period of time.” The therapy is generally well tolerated. Efforts are ongoing to identify the best ways to proactively and reactively use prednisone to manage side effects such as mild increases in transaminase levels. To date, the risk-benefit profile appears reasonable for patients with clotting factor IX deficiency, and it is likely that the therapy in that setting “will march toward the regulatory process to determine if it’s safe and effective for approval,” he said. Responses in those with clotting factor VIII deficiency have been more variable, with some patients requiring long-term prednisone use, which is problematic. More information is needed about this, but investigation is ongoing, he said. Registries are available and many companies are involved in clinical trials. Clinicians and patients can look for information at clinicaltrials.gov, wfh.org (which publishes trial results and conducts workshops and meetings), and at the US National Hemophilia Foundation (Hemophilia.org) and the Society of Thrombosis and Hemostasis (ISTH.org). Show notes written by Sharon Worcester, MA, a reporter for MDedge and Medscape. Disclosures Dr. Henry has no relevant disclosures. Dr. Pierce disclosed relationships with Ambys Medicines, BioMarin, BridgeBio, CRISPR Therapeutics, Decibel Therapeutics, Frontera, Geneception, Generation Bio, Novo Nordisk, Pfizer, Regeneron, Third Rock Ventures, Voyager Therapeutics, Global Blood Therapeutics, VarmX SAB, the National Hemophilia Foundation Medical and Scientific Advisory Council, and the World Federation of Hemophilia. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd  

At least 17 cases of thrombosis and thrombocytopenia have been reported in patients who received the Johnson & Johnson COVID-19 vaccine in the United States. Such events have been reported in patients who received the AstraZeneca vaccine as well. In this episode, Adam C. Cuker, MD, of the University of Pennsylvania, Philadelphia, tells host David H. Henry, MD, how to identify and manage patients with these vaccine-induced events. What’s in a name? The phenomenon of vaccine-induced thrombosis and thrombocytopenia has been given different names, including: Vaccine-induced immune thrombotic thrombocytopenia (VITT) Vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) Thrombosis and thrombocytopenia syndrome (TTS). Dr. Cuker’s preferred acronym is VITT. VITT is an immune-mediated reaction to the Johnson & Johnson and AstraZeneca vaccines that “results in thrombocytopenia and a strong propensity for thrombosis,” Dr. Cuker explained. Dr. Henry noted that VITT is reminiscent of heparin-induced thrombocytopenia (HIT). Incidence unclear VITT appears to be “very rare,” but “we still don't have a great sense of how common it is” because additional cases may not have been recognized or have yet to present, Dr. Cuker said. VITT occurs about 5-30 days after vaccination. VITT appears to be mediated by IgG antibodies, which take time to build up. The exact mechanism is unknown, but VITT could be related to the adenovirus vector used in the Johnson & Johnson and AstraZeneca vaccines, Dr. Cuker said. The first 15 cases of VITT associated with the Johnson & Johnson vaccine occurred in women, and most patients were aged under 50 years. In Canada, where the AstraZeneca vaccine is available, cases of VITT have been reported in patients in their 80s and 90s. Diagnosing VITT Symptoms of VITT can include severe, unrelenting headache; severe abdominal pain; nausea and vomiting; as well as typical signs and symptoms of deep vein thrombosis or pulmonary embolism. To determine if a patient has VITT, Dr. Cuker recommends ordering a disseminated intravascular coagulation panel – prothrombin time, partial thromboplastin time, fibrinogen, and D-dimer – as well as a standard HIT enzyme-linked immunosorbent assay (ELISA). Rapid immunoassays for HIT are not reliable for VITT, so HIT ELISA must be used, Dr. Cuker emphasized. Most patients with VITT have a “strongly positive” ELISA with optical density values “well in excess of 100 or 1.0,” depending on the scale, Dr. Cuker said. Manage VITT like HIT Patients should receive an anticoagulant, but not heparin, Dr. Cuker said. It isn’t clear if heparin will be harmful in patients with VITT, but current guidelines recommend avoiding heparin. He also advised against using warfarin or vitamin K antagonists in patients with VITT “at least until their platelet count recovers.” High-dose intravenous immunoglobulin (e.g., 1 g/kg for 2 consecutive days) is recommended, as it is believed to interfere with platelet activation. Show notes written by M. Alexander Otto, a reporter for MDedge and Medscape. Disclosures Dr. Henry has no relevant disclosures. Dr. Cuker has served as a consultant for Synergy Pharmaceuticals; has received authorship royalties from UpToDate; and his institution has received research support on his behalf from Alexion, Bayer, Novartis, Novo Nordisk, Pfizer, Sanofi, Spark Therapeutics, and Takeda. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

The combined clinical cell-cycle risk (CCR) score uses clinical and genetic factors to assess the risk of metastasis after radiation therapy in patients with prostate cancer. The CCR score has proven accurate in studies and can guide post-radiation treatment decisions in practice, according to Jonathan D. Tward, MD, PhD, of the University of Utah, Salt Lake City. Dr. Tward discusses the CCR score with host David Henry, MD, in this episode. About the score The CCR score combines the cell-cycle progression (CCP) score (available commercially as the Prolaris test) and the Cancer of the Prostate Risk Assessment (CAPRA) score to more precisely determine the postradiation risk for metastatic disease. Investigators identified a threshold for determining precise risk levels (2.112), which allows for personalized treatment decision-making based on more individual characteristics than standard risk-group categorizations, according to Dr. Tward. He noted that standard risk groups can include a broad range of actual risk even within a given category. Risk groups are “reasonably good at prognosticating who may or may not go on to have metastasis etc., but they’re not that good,” Dr. Tward said. CCR score proves effective Dr. Tward and colleagues evaluated the CCR score in a retrospective study published in Clinical Genitourinary Cancer (https://bit.ly/3vlgUwe). The study included 718 men with intermediate- or high-risk localized prostate cancer who received single modality or multimodality therapy. Results showed that patients with CCR scores below the identified threshold (2.112) could safely forgo multimodality therapy. CCR score bests other scoring systems In another study, the CCR score proved more accurate than other scoring systems. Dr. Tward presented findings from this study at the 2021 Genitourinary Cancers Symposium (https://bit.ly/3eBvAjM). The study included 741 men with intermediate- or high-risk localized prostate cancer who received single modality or multimodality therapy. The CCR score predicted metastasis (hazard ratio, 2.21; C-index, 0.78) and did so better than National Comprehensive Cancer Network risk groups (C-index, 0.70), the CAPRA score alone (C-index, 0.71), or the CCP score alone (C-index, 0.69). Dr. Tward said he has used the CCR score in his own practice for years and found it helpful. Show notes written by Sharon Worcester, a reporter for MDedge and Medscape. Disclosures Both studies were funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics and other companies. Dr. Henry has no relevant disclosures. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd 

Pediatric oncologists are used to dealing with emotional, heart-wrenching situations, but oncology took on a new dimension for Michael Weiner, MD, when both he and his daughter were diagnosed with cancer. Dr. Weiner, a pediatric oncologist at Columbia University, New York, describes his roles as oncologist, patient, and caregiver to host David H. Henry, MD, in this episode.  Oncologist as patient: Lessons learned Dr. Weiner’s journey as a cancer patient began when he felt a lymph node on his neck that he knew wasn’t “normal.” A colleague examined Dr. Weiner and suggested the “watch-and-wait” approach, but Dr. Weiner insisted on immediate biopsy. The diagnosis was follicular lymphoma, and Dr. Weiner had a hard time accepting that his malignancy was treatable but not curable. One of the things Dr. Weiner learned as a cancer patient is that “you really need to connect with your doctor,” so he chose a doctor who felt like a good fit for him. Another lesson Dr. Weiner learned was that cancer can be very isolating. Though friends and family can offer help and support, “you take this journey alone,” he said. Dr. Weiner was treated with rituximab and radiation, which proved successful. It’s been 3 years since he completed his treatment. Dr. Weiner had been reluctant to undergo radiation because of the risk of thyroid cancer, and, unfortunately, he now has a small thyroid nodule that’s under observation. Update: After this episode was recorded, Dr. Weiner was diagnosed with papillary thyroid cancer. He is set to undergo a total thyroidectomy. Oncologist as caregiver: Taking a backseat Dr. Weiner’s daughter was diagnosed with papillary thyroid carcinoma after a nodule was found on a routine exam. Dr. Weiner and his daughter decided to educate themselves about her malignancy and opted for an aggressive course of treatment. “I tried very, very hard to be a parent and not a physician,” Dr. Weiner said. He decided to put his faith in her care team. “I in no way participated in the final decision-making,” he said. His daughter ultimately had a total thyroidectomy and high-dose radioactive iodine. The process, like his own cancer journey, was difficult. Dr. Weiner recounts these experiences in his book “Living Cancer: Stories from an Oncologist, Father, and Survivor,” which can be found here: https://bit.ly/3n7TB5Z. Show notes written by M. Alexander Otto, a reporter for MDedge and Medscape. Disclosures Dr. Weiner and Dr. Henry have no relevant disclosures. These show notes were updated on 4/22. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

Studies have shown that chimeric antigen receptor (CAR) T-cell therapies produce responses in patients with relapsed/refractory B-cell lymphomas, but researchers continue to look for ways to improve efficacy, decrease toxicity, and overcome treatment resistance. Leslie Kean, MD, PhD, of Boston Children’s Hospital, discusses some of this research with host David H. Henry, MD, in this episode. Dr. Kean outlines four recent studies of CAR T-cell therapies in lymphoma. The studies were selected as part of the “Best of ASH” session at the 2020 annual meeting of the American Society of Hematology. Primary Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Indolent Non-Hodgkin Lymphoma This study was designed to assess the efficacy and safety of axicabtagene ciloleucel (axi-cel) in patients with indolent lymphomas. In follicular lymphoma, the overall response rate (ORR) was 94%, and the complete response (CR) rate was 80%. In marginal zone lymphoma, the ORR was 85%, and the CR rate was 60%. There was one grade 5 and one grade 4 case of cytokine release syndrome (CRS). Dr. Kean noted that 146 patients were evaluable for adverse events, so the single death related to CRS should be viewed in that context. Overall, 82% of patients had CRS of any grade. Jacobson C et al. ASH 2020, Abstract 700. https://bit.ly/32at91V. What’s involved in a CAR T-cell study? Dr. Kean explained that a patient is first deemed eligible by an oncologist and then enrolled in a CAR T-cell study. For studies like ZUMA-5 that are testing autologous CAR T cells, basic lab work is done to ensure the patient has a high enough lymphocyte count. The patient then undergoes apheresis, and the patient’s T cells are used to create the CAR T-cell product. The company developing the product transduces the T cells with the CAR so the resulting CAR T cells will target cancer cells. The therapy in ZUMA-5, axi-cel, targets CD19, which is expressed on B-cell lymphoma cells. Normal B cells express CD19 as well, so immunoglobulin replacement is sometimes necessary to offset the loss of normal B cells. Efficacy and Safety of Tisagenlecleucel in Adult Patients with Relapsed/Refractory Follicular Lymphoma: Interim Analysis of the Phase 2 ELARA Trial Tisagenlecleucel differs from axi-cel in the signaling domain, though tisagenlecleucel targets CD19 as well, Dr. Kean explained. She noted that tisagenlecleucel is a bit more long-lived than axi-cel. In this trial, tisagenlecleucel produced an ORR of 82% and a CR rate of 65%. There were no cases of grade 3 or higher CRS, which may be attributed to the different signaling domain, Dr. Kean said. Fowler NH et al. ASH 2020, Abstract 1149. https://bit.ly/2OIGjjA. TRANSCEND CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel (liso-cel) in Combination with Ibrutinib for Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Patients in this study received the CAR T-cell therapy liso-cel in combination with the BTK inhibitor ibrutinib. The combination increased both efficacy and safety, as ibrutinib assisted in calming down the immune response. There were no grade 5 adverse events and no cases of grade 4 CRS or neurotoxicity. The ORR was 95%, and the CR rate was 63%. There was no difference in response among patients who had or had not received a BTK inhibitor previously, Dr. Kean noted. Wierda WG et al. ASH 2020, Abstract 544. https://bit.ly/3uPuJ5U. CD58 Aberrations Limit Durable Responses to CD19 CAR in Large B Cell Lymphoma Patients Treated with Axicabtagene Ciloleucel But Can Be Overcome Through Novel CAR Engineering Dr. Kean noted that CAR T-cell therapy typically produces a CR in more than 90% of patients within 30 days, but the long-term duration of response is about 50%. With this study, researchers wanted to investigate why a CAR T-cell therapy would fail and determine if any tumor-specific factors affect the duration of response. The team found that patients who had mutations in CD58 were less likely to achieve a CR to axi-cel, and most patients with these mutations ultimately progressed. CD2, the T-cell ligand for CD58, plays adhesive and costimulatory roles in T cells, and CAR T cells rely on intrinsic T-cell signaling to work, Dr. Kean explained. So if the CD2 in a CAR T cell can’t “see” CD58 on the tumor because of a mutation, the CAR T cell doesn’t work, she added. To bypass this, the researchers created a construct integrating CD2 costimulatory domains within the CAR molecule so it expressed CD2 in a way that doesn’t require CD58. The new construct “cures tumors like gangbusters” in mouse models, Dr. Kean said, adding that this CAR T-cell therapy could be coming to the clinic soon. Maizner RG et al. ASH 2020, Abstract 556. https://bit.ly/3283zL0. Looking ahead: Concerns about cost Cost is a critical barrier to receiving CAR T-cell therapy, Dr. Kean noted, especially for patients who require additional treatment after receiving CAR T cells. The next generation of CAR T-cell research should determine if this treatment is best used as a bridge to transplant or if CAR T-cell therapy can stand alone, she added. To make the cost more palatable, CAR T-cell products should be a final cure, Dr. Kean said. Show notes written by Malika Gill, MD, a resident at Pennsylvania Hospital, Philadelphia. Disclosures Dr. Henry has no relevant disclosures. Dr. Kean disclosed relationships with Magenta Therapeutics, Bristol-Myers Squibb, Kymab, HiFiBiO Therapeutics, Regeneron, Novartis, Gilead, Bluebird Bio, and Forty Seven. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

Researchers have tracked the evolution of genetic germline testing in women with breast or ovarian cancer in recent years and reported the results in the Journal of Clinical Oncology. Study author Allison W. Kurian, MD, of Stanford (Calif.) University, describes the group’s findings (https://bit.ly/31RaSGR) to guest host Alan Lyss, MD, subprincipal investigator emeritus for Heartland Cancer Research NCORP, in this episode. Study rationale and methods Dr. Kurian said that an inflection point for breast cancer genetics was in 2013 when the U.S. Supreme Court ruled that gene patenting was not allowed for the purposes of genetic testing. As a result, the cost of testing BRCA1/2 genes fell, and testing became much more accessible. With their study, Dr. Kurian and colleagues aimed to look at trends following the increase in accessibility. The researchers used Surveillance, Epidemiology, and End Results Program (SEER) records of women aged 20 years and older who were diagnosed with breast or ovarian cancer from 2013 to 2017 in California or Georgia. The team linked these data to results of clinical germline testing through 2019. Dr. Kurian explained that the SEER data are comprehensive enough that all cancer cases in California and Georgia were likely included, the states provide a large catchment area of about 50 million people, and the states have different kinds of racial/ethnic diversity and urban/rural distribution. The researchers used the data to assess testing trends as well as rates of variants of uncertain significance (VUS) and pathogenic variants (PVs). Results by hypothesis Hypothesis 1: Multigene panels will entirely replace testing for BRCA1/2 only. This hypothesis was essentially correct. Testing of only two genes was almost totally replaced by testing many more genes. The number of genes tested for breast cancer increased annually by 28% over the study period. Hypothesis 2: Underutilization of testing patients with ovarian cancer will improve over time. It is standard of care to recommend genetic testing for all ovarian cancer patients. Based on 2013-2014 data, only one-third of women were tested. As tests became more accessible in subsequent years, the hope was that more women would be tested. Unfortunately, there was very little improvement in testing rates over the study period. Hypothesis 3: More patients will be tested at lower levels of pretest risk for PVs. In patients aged older than 60 years, testing rates increased for breast cancer (from 11% to 15%) and ovarian cancer (from 25% to 31%). Patients aged younger than 45 years had lower testing rates over time, however. Dr. Kurian noted that about 33% of ovarian cancer patients undergo genetic testing, but the goal is 100%. It is unclear if the goal should be 100% for breast cancer, Dr. Kurian said. Hypothesis 4: Sociodemographic difference in testing trends would not be seen. There was not much of a gap observed with breast cancer patients. For example, among patients with breast cancer, approximately 31% of those who had genetic testing were uninsured, 31% had Medicaid, and 26% had private insurance or Medicare. There is more of an equity issue with ovarian cancer. About 28% of those who had genetic testing were uninsured, 27% had Medicaid, and 39% had private insurance or Medicare. Dr. Kurian said disparities in ovarian cancer persist in patients who are uninsured and those in certain racial/ethnic groups, including African Americans. These patients are less likely to get genetic testing. Hypothesis 5: Detection of PVs and VUS will increase. The detection of VUS increased at a higher rate in comparison with PVs when more genes were being tested. This is likely because of the fact that, for every PV you find, you will find many more VUS, Dr. Kurian said. Hypothesis 6: Racial or ethnic disparities in rates of VUS will diminish over time. Disparities actually increased over the study period as more genes were tested. Some studies have suggested that VUS results lead to unnecessary prophylactic surgery, Dr. Kurian said. She added that the decision to undergo prophylactic surgery should not be based on a VUS because “the great majority of VUS turn out to be nothing.” Additional findings and implications for practice The study revealed that most PVs were in 20 genes associated with breast or ovarian cancer. Dr. Kurian and colleagues concluded that the way to improve testing is to focus on those 20 genes and ensure appropriate patients are being tested, rather than adding more genes to tests. Dr. Kurian said it is urgent to increase genetic testing in patients with ovarian cancer, as it is not being done at the rate it should be. Dr. Kurian also noted that one positive outcome of the COVID-19 pandemic has been an increase in telehealth visits and at-home genetic testing. Providing patients with these more convenient options could increase the use of genetic testing. Show notes written by Alesha Levenson, MD, a resident at Penn Medicine, Philadelphia. Disclosures Dr. Kurian disclosed relationships with Myriad Genetics, Ambry Genetics, Color Genomics, GeneDx/BioReference, InVitae, and Genentech. The study was supported by the National Cancer Institute, the Centers for Disease Control and Prevention, and the California Department of Public Health. Dr. Lyss writes a column for MDedge Hematology/Oncology called “Clinical Insights” (https://bit.ly/3m76xIP). He has no other conflicts of interest. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc Dr. Lyss on Twitter: @HeartlandOncDoc

A program called Drive By Flu-FIT has allowed for socially distanced colorectal cancer (CRC) screening during the COVID-19 pandemic. Armenta Washington, senior research coordinator at the University of Pennsylvania, describes the program to guest host Alan Lyss, MD, subprincipal investigator emeritus for Heartland Cancer Research NCORP, in this episode. What is Drive By Flu-FIT? Drive By Flu-FIT is a socially distanced version of the Flu-Fecal Immunochemical Test (Flu-FIT) program. Flu-FIT was designed to increase access to CRC screening by offering take-home FIT tests to patients at the time of their annual flu shots. The goal of Drive By Flu-FIT is to provide a COVID-safe approach to CRC screening and counteract the decrease in CRC screening seen during the pandemic. Drive By Flu-FIT is a joint effort of the University of Pennsylvania, the Einstein Healthcare Network, Chi Eta Phi Sorority, and Enon Tabernacle Baptist Church, the largest Baptist church in the Philadelphia region. How does Drive By Flu-FIT work? To participate in a Drive By Flu-FIT event, community members had to complete eligibility, registration, and demographic questionnaires online. Patients who were enrolled watched a short educational video on CRC and completed two questionnaires – one on CRC screening knowledge (14 items) and one on screening intentions (5 items) – before and after watching the video. At the Drive By Flu-FIT events, patients remained in their cars while physicians in personal protective equipment handed out FITs and explained how to use them and return them. Patients could also receive a flu vaccine at each event. Results: High return rate According to initial data, 335 patients registered for a Drive By Flu-FIT event, but 80 (23.9%) ultimately didn’t attend and 63 (18.8%) were found to be ineligible. A total of 192 patients attended and received a FIT (57.3%). Scores on both questionnaires increased after patients watched the educational video. Patients’ baseline knowledge of CRC was high but lacking in four areas: risk factors for CRC, the optimal frequency of FITs, the link between Lynch syndrome and CRC, and the relationship between physical activity and CRC risk. Of the 192 patients who received a FIT, 38 (19.7%) did not return it. There were 141 patients (73.4%) with a negative FIT result, while 13 (6.7%) had a positive FIT result and were referred for colonoscopy. Resources For more information on Flu-FIT, visit http://flufit.org/. For more details on Drive By Flu-FIT, see: AACR Virtual Meeting: COVID-19 and Cancer, Abstract S02-04: https://bit.ly/3szf0Hp. MDedge coverage of the meeting presentation: https://bit.ly/3szfrl1. Ms. Washington disclosed no conflicts of interest. The study was supported by the National Cancer Institute. The FITs were donated by Polymedco, and the flu vaccines were donated by the Philadelphia Public Health Department. Dr. Lyss writes a column for MDedge Hematology/Oncology called “Clinical Insights” (https://bit.ly/3m76xIP). He has no other conflicts of interest. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc Dr. Lyss on Twitter: @HeartlandOncDoc

Earlier this year, clinical practice guidelines for the diagnosis and management of von Willebrand disease (VWD) were published in Blood Advances. The guidelines (https://bit.ly/2OIfKLE) are a collaborative effort from the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. Guideline author Paula James, MD, of Queens University, Kingston, Ont., reviews some of the recommendations in these guidelines with host David H. Henry, MD, in this episode. Case discussion A patient presents with the complaint of heavy menstrual bleeding, which could indicate a bleeding disorder such as VWD. How does one diagnose or rule out VWD? Tests to order include CBC, prothrombin time (PT), and partial thromboplastin time (PTT). Results of CBC, PT, and PTT could be normal, which would necessitate special testing to specifically look at factor VIII and von Willebrand factor (VWF). A patient’s family history may be helpful, as most types of VWD are autosomal dominant, though two subtypes are recessive. Diagnostic evaluation of VWD VWF is the chaperone protein for factor VIII in the intrinsic pathway, which is measured by the PTT. In more severe forms of VWD, the PTT is prolonged because of factor VIII. VWF is measured separately because it is not reflected in the PT or PTT. The recommendation is to measure VWF antigen and employ a functional assay to see how well VWF binds platelets. The recommendation in the new guidelines is to use the GPIbM assay rather than the ristocetin cofactor assay. Many labs in the United States are still using the ristocetin cofactor assay. However, in Canada, Europe, and other parts of the world, many labs have moved to a newer assay that is automated. It has a much lower coefficient of variation and fewer issues with measurement of VWF in Black populations, which is a major issue with the cofactor assay. Types of VWD Type 1 VWD is characterized by a decreased amount of VWF. Type 1 patients have low VWF antigen and low platelet-dependent VWF function to a similar degree, with low or normal factor VIII. Type 2 VWD is characterized by aberrant VWF. The functional assay is a lot lower than VWF antigen. The platelet-dependent function to VWF antigen ratio cutoff is 0.7. Further testing is warranted to determine subtypes (2A, 2B, 2N, or 2M), including VWF multimers. Genetic testing can be helpful to further delineate subtypes. Type 3 VWD is characterized by the absence of VWF. The patient will have a VWF antigen level of 0, platelet-dependent VWF function of 0, and a reduced factor VIII level (usually less than 10%). Pregnant patients with VWD There is a protective adaptation in pregnancy, in which factors normalize in the third trimester, which works to prevent hemorrhage at delivery. This protective effect is because of the hormonal changes of pregnancy, and it is seen in patients with milder forms of VWD. WVF levels peak within 8-24 hours after delivery and then slowly return to baseline. There is a risk of delayed postpartum hemorrhage once VWF levels return to baseline, which tends to happen 7-14 days postpartum. Procedural planning: Desmopressin challenge test Desmopressin causes the release of VWF from the Weibel-Palade bodies of the endothelium, and it can be used as prophylaxis or treatment of bleeding in type 1 VWD. The desmopressin challenge test is used to check how the patient responds to desmopressin when well, to predict the patient’s response after an anticipated procedure. The test involves measuring VWF levels before desmopressin is given and at 1 hour, 2 hours, and 4 hours after desmopressin administration. The idea is to measure the magnitude of increase in VWF levels and observe how sustained that increase is to predict the patient’s response to desmopressin after future procedures. There is a subset of patients with type 1 VWD who have increased clearance of VWF that causes their decreased VWF levels. They may not have a sustained plateau in the VWF level after desmopressin, which emphasizes why testing as far as 4 hours after desmopressin administration is important. The dose of desmopressin given in this test is typically 0.3-0.4 mcg/kg. Recommendations for preprocedure prophylaxis for type 1 VWD Minor procedures (e.g., wisdom tooth extraction) The patient should receive an antifibrinolytic agent, such as tranexamic acid or aminocaproic acid, 2 hours before the procedure, followed by desmopressin 30-60 minutes prior to the procedure. After the procedure, the patient should continue to receive the antifibrinolytic agent for 3-4 days. Major procedures/surgeries (e.g., gallbladder removal) The guidelines do not recommend desmopressin for major procedures because patients need to be fluid-restricted for approximately 24 hours after administration because of the risk of hyponatremia. Desmopressin is a synthetic analog of vasopressin, which results in the accumulation of free water similarly to vasopressin. The guidelines do recommend giving VWF-containing concentrate to increase VWF and factor VIII to greater than 50% from baseline for at least 3 days. VWF concentrates can be given every 12 hours or as continuous intravenous infusions. Tranexamic acid should be given as an adjuvant both prior to the procedure and in the days following. Cryoprecipitate is not recommended because it can’t be virally inactivated.  Preprocedure prophylaxis in type 2 or 3 VWD Desmopressin does not work for most patients with type 2 or 3 VWD. So even for minor procedures, these patients will need to receive VWF concentrate coupled with antifibrinolytics. Show notes written by Sheila DeYoung, DO, a resident at Pennsylvania Hospital, Philadelphia. Disclosures Dr. Henry has no relevant disclosures. Dr. James disclosed relationships with Baxter/Baxalta/Shire, CSL Behring, Bayer, and Octapharma. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: [email protected] Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd