Episodes
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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.
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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.
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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.
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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.
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).
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?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.* * *
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David Henry on Twitter: @davidhenrymd
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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.
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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.* * *
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David Henry on Twitter: @davidhenrymd
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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.
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.
Primary Analysis of ZUMA-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory Indolent Non-Hodgkin LymphomaWhat’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.* * *
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David Henry on Twitter: @davidhenrymd
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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.
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Email the show: [email protected]
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Dr. Lyss on Twitter: @HeartlandOncDoc
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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.
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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.
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We continue our review of drugs recently approved by the Food and Drug Administration (FDA) in the hematology/oncology space.
In part 1 of our review, David M. Mintzer, MD, of Pennsylvania Hospital, highlighted 11 therapies, including newly-approved treatments and new indications for older drugs. Part 1 was published Feb. 18 (https://bit.ly/38JR782).
Now, in part 2, Dr. Mintzer tells host David H. Henry, MD, about another 11 therapies recently approved by the FDA, including monoclonal antibodies, kinase inhibitors, chimeric antigen receptor (CAR) T-cell therapies, and more.
Margetuximab-cmkb (Margenza)In Dec. 2020, margetuximab-cmkb was approved for use in combination with chemotherapy to treat adults with metastatic, HER2-positive breast cancer who had received at least two prior anti-HER2 regimens, including at least one for metastatic disease. https://bit.ly/38JAiKg
Tafasitamab-cxix (Monjuvi)In July 2020, tafasitamab-cxix received accelerated approval for use in combination with lenalidomide to treat adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low-grade lymphoma, who are not eligible for autologous stem cell transplant. https://bit.ly/3vtiHQF
Lurbinectedin (Zepzelca)In June 2020, lurbinectedin received accelerated approval to treat adults with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. https://bit.ly/30KcnpB
Belantamab mafodotin-blmf (Blenrep)In Aug. 2020, belantamab mafodotin-blmf received accelerated approval to treat adults with relapsed or refractory multiple myeloma who had received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. https://bit.ly/3lkPLWd
Umbralisib (Ukoniq)In Feb. 2021, the FDA granted umbralisib accelerated approval to treat adults with relapsed or refractory marginal zone lymphoma who had received at least one prior anti-CD20-based regimen and adults with relapsed or refractory follicular lymphoma who had received at least three prior lines of systemic therapy. https://bit.ly/3bQqtMM
Azacitidine tablets (Onureg)In Sept. 2020, the FDA approved azacitidine tablets for continued treatment of patients with acute myeloid leukemia who had achieved a first complete remission or complete remission with incomplete blood count recovery after intensive induction chemotherapy and who are not able to complete intensive curative therapy. https://bit.ly/38KFT2Z
Decitabine and cedazuridine tablets (Inqovi)In July 2020, the FDA approved an oral combination of decitabine and cedazuridine to treat adults with myelodysplastic syndromes (MDS). This includes previously treated and untreated, de novo and secondary MDS (including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia), as well as intermediate-1, intermediate-2, and high-risk MDS. https://bit.ly/3lmqlI4
Tepotinib (Tepmetko)In Feb. 2021, the FDA granted accelerated approval to tepotinib for adults with metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping alterations. https://bit.ly/3lmqBXy
Pralsetinib (Gavreto)In Sept. 2020, pralsetinib received accelerated approval to treat adults with metastatic RET fusion-positive NSCLC. https://bit.ly/3vrS26I
In Dec. 2020, the FDA granted full approval to pralsetinib to treat adult and pediatric patients ages 12 and older with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy or those with RET fusion-positive thyroid cancer who require systemic therapy and are refractory to radioactive iodine. https://bit.ly/3eCVXrs
Brexucabtagene autoleucel (Tecartus)In July 2020, the FDA granted accelerated approval to brexucabtagene autoleucel, a CD19-directed CAR T-cell therapy, for the treatment of adults with relapsed or refractory mantle cell lymphoma. https://bit.ly/3tBtqH9
Lisocabtagene maraleucel (Breyanzi)In Feb. 2021, another CD19-directed CAR T-cell therapy, lisocabtagene maraleucel, was approved to treat adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. The approval encompasses DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. https://bit.ly/3lljHBx
DisclosuresDr. Mintzer and Dr. Henry have no relevant disclosures.
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Treatments for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) have advanced in recent years, with more new developments on the horizon.
James Gerson, MD, of the University of Pennsylvania, Philadelphia, reviewed some of these advances and future directions while describing how he would treat three patients. Host David H. Henry, MD, posed the following cases for consideration.
Case 1
In a 75-year-old male with no comorbid illness, routine blood work revealed a WBC count of 15,000/mcL. The manual differential showed mature lymphocytes and smudge cells. The patient has no constitutional symptoms, but there is suspicion of CLL. What to do?
An incidental finding of elevated WBC is the most common presentation for CLL, Dr. Gerson noted. Flow cytometry is how most diagnoses are made. If the patient’s blood sample is CD5+ and CD20+, in the vast majority of cases, the patient has CLL. The main alternative diagnosis is MCL, so Dr. Gerson recommends checking for cyclin-D1 overexpression and translocation (11;14), which would be present in MCL. Dr. Gerson also recommends fluorescence in situ hybridization (FISH), cytogenetics, and next-generation sequencing to assist with prognostication. When the exam is normal and the patient is asymptomatic, no imaging is required. For this patient, treatment should be deferred until disease progression.Case 2
A 75-year-old, fit male has a WBC of 25,000/mcL, noted after the patient reported not feeling well, having a distended abdomen, night sweats, and weight loss. Blood work shows a hemoglobin level of 10.5 g/dL and a platelet count of 130 x 103/mcL. What to do?
Because this patient is symptomatic, treatment is indicated, Dr. Gerson said. However, because of the pandemic, Dr. Gerson would likely delay therapy, perhaps until after COVID-19 vaccination. To assess risk, Dr. Gerson would perform immunohistochemistry, FISH, and next-generation sequencing in this patient. Patients with 17p deletion have high-risk disease, those with TP53 missense or nonsense mutations have even higher-risk disease, and patients with both a deletion and a mutation are “at excessively high risk,” Dr. Gerson said. He favors giving a BTK inhibitor to patients with TP53 mutation/17p deletion because of results from the CLL14 trial (N Engl J Med 2019; 380:2225-36. https://bit.ly/38pVHbf). However, because of the “small signal” in the trial, Dr. Gerson said plenty of his colleagues use a BTK inhibitor interchangeably with a BCL2 inhibitor and anti-CD20 therapy (e.g., venetoclax and obinutuzumab). Dr. Gerson said ibrutinib and acalabrutinib have similar efficacy, according to unpublished results of the ELEVATE-RR trial (https://bit.ly/38onIjy). Both drugs inhibit platelets, and there appears to be a higher risk of atrial fibrillation with ibrutinib.Case 3
A 75-year-old, fit male has an elevated WBC, noted after complaints of bone pain, weight loss, night sweats, and enlarged lymph nodes. There is suspicion of MCL. What to do?
MCL is a complicated disease and “incredibly” heterogeneous in clinical and pathological behavior, Dr. Gerson noted. The classic finding in MCL is cyclin-D1 overexpression caused by (11;14) translocation, but there are atypical translocations as well. The approach to first-line treatment of MCL varies and may include cytarabine-based induction, bendamustine plus rituximab, or rituximab alone. Brexucabtagene autoleucel, a chimeric antigen receptor T-cell therapy, is changing the landscape of treatment for relapsed/refractory MCL, Dr. Gerson said, as this treatment may offer a cure. Investigational therapies for MCL include the BTK inhibitor pirtobrutinib (LOXO-305) and hematopoietic stem cell transplant. Pirtobrutinib is under investigation in patients with MCL, CLL, and other indolent lymphomas that have progressed on or are intolerant to first-line therapy (Lancet. 2021 Mar 6;397[10277]:892-901. https://bit.ly/3rvRv1h).Show notes written by Ronak Mistry, DO, a resident at Pennsylvania Hospital, Philadelphia.
Disclosures
Dr. Gerson disclosed relationships with Loxo Oncology, Genentech, Pharmacyclics, and TG Therapeutics. Dr. Henry has no relevant disclosures.
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When should cancer patients receive a COVID-19 vaccine? The National Comprehensive Cancer Network (NCCN) has issued recommendations to provide guidance on the topic.
Prioritization for COVID-19 vaccination should be given to cancer patients currently receiving chemotherapy, those who just finished active treatment, or those about to receive treatment. Additional factors that should be taken into consideration include age, comorbidities, and sociodemographic characteristics.
Guideline author Steven Pergam, MD, of Fred Hutchinson Cancer Research Center, Seattle, explains NCCN’s recommendations to host David H. Henry, MD, in this episode.
PrioritizationTransplant and cellular therapy
Patients who undergo allogeneic or autologous transplant or those who receive cellular therapy should be vaccinated at least 3 months after this treatment. This recommendation is based on best practices used for other vaccines, as there are insufficient data on COVID-19 vaccination in these patients, Dr. Pergam noted.Hematologic malignancies
For patients with hematologic malignancies receiving intensive cytotoxic chemotherapy, vaccination should be delayed until absolute neutrophil count recovery. Patients with marrow failure from disease, those receiving therapy expected to have limited or no recovery, and those on long-term maintenance therapy should get vaccinated when a vaccine is available to them.Antibody response
There are no current data to support checking antibodies prior to vaccination, as one will lose antibodies over time, Dr. Pergam noted. Likewise, there are no data to support testing for antibodies after vaccination.Solid tumor malignancies
Patients with solid tumor malignancies who are receiving cytotoxic chemotherapy, targeted therapy, radiation, or checkpoint inhibitors or other immunotherapies should be vaccinated when a vaccine is available to them. For patients undergoing surgery, there should be adequate time between receiving a vaccine and the surgical date, as side effects from the vaccine, such as fever, can delay surgery.These guidelines are available for download from the NCCN website: https://www.nccn.org/covid-19/.
Show notes written by Malika Gill, MD, a resident at Pennsylvania Hospital, Philadelphia.
Disclosures
Dr. Pergam and Dr. Henry have no relevant disclosures.
For more MDedge Podcasts, go to mdedge.com/podcasts
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David Henry on Twitter: @davidhenrymd
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Ifeyinwa (Ify) Osunkwo, MD, MPH, joins us to talk about her approach to pain management in patients suffering from sickle cell crisis as well as the cognitive and behavioral effects of long-term opioid use in these patients. She and our host David H. Henry, MD, cover these topics and more in this episode.
Dr. Osunkwo is a professor of medicine at Atrium Health and the director of the Sickle Cell Enterprise at the Levine Cancer Institute, part of Atrium Health, in Charlotte, N.C.
Over the course of a decade, the life expectancy of patients with sickle cell disease has increased. Today 99% of children with sickle cell disease will live to become adults. When treating patients with sickle cell pain it is important to consider their disease trajectory, and to weigh the pros and cons for initiation of opioid therapy.Management of sickle cell disease in the acute setting:
In children, therapy usually includes use of intravenous fluid and intravenous opioids, then an eventual transition to oral opioids and NSAIDS. In adolescents, exposure to a prolonged course of high-dose opioids actually has been shown to exacerbate their pain. PCA (patient-controlled analgesia) versus “PRN” or as-needed medications removes the dependency on the external environment to receive pain medications and lessens the degree of psychological stress in these patients. Use of intravenous ketamine as an adjuvant to opioids in patients with an acute exacerbation has been shown to improve outcomes in patients (i.e., better pain control, decreased hospital stay, and management of anxiety and stress of a pain crisis.) In the acute pain setting, it is important to go through all differentials to get to where you are treating the right cause of pain. Following hospitalization, these patients often present back to the hospital in subacute opioid withdrawal. The key here is to engage patients in long term treatment plans. For opioid-induced itching, it has been shown that in patients who receive intravenous Benadryl have worse outcomes than in patients that receive oral Benadryl.Long-term side effects of chronic opioid therapy use:
Psychological and behavioral side effects including insomnia, reduced libido, tolerance, oppositional behavior, poor memory, psychosis, paranoia, increased depression/anxiety and confusion. The opioid risk score is a helpful screening test that looks at the risk of adverse opioid outcomes. Specifically, family history of substance abuse, personal history of substance abuse, history of person abuse or psychological diagnosis results in a higher score which correlates with a higher risk of negative outcomes. Use of suboxone has proved to be very beneficial in patients on chronic opioid therapy in preventing frequent hospitalizations.Show notes written by Alesha Levenson, MD, a resident with Penn Medicine, Philadelphia.
Disclosures
Dr. Osunkwo disclosed relationships with Terumo, Global Blood Therapeutics, Acceleron, FORMA Therapeutics, Health Resources and Services Administration, Patient Centered Outcomes Research Institute, Micella Biopharma, Pfizer, and Novartis. Dr. Henry has no relevant disclosures.
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In this episode, we review drugs recently approved by the Food and Drug Administration in the hematology/oncology space.
David M. Mintzer, MD, of Pennsylvania Hospital, joins host David H. Henry, MD, to highlight some first-time approvals and new indications for older drugs.
First-line treatment of patients with unresectable or metastatic microsatellite instability–high or mismatch repair deficient colorectal cancer. https://bit.ly/2OKw8uF. Treatment of adult and pediatric patients who have tumor mutational burden–high (≥10 mutations/megabase) solid tumors that progressed after prior treatment and who have no satisfactory alternative treatment options. https://bit.ly/2NCddkX. For use in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (combined positive score ≥10) as determined by an FDA-approved test. https://bit.ly/2ZobcMc. To treat patients with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation. https://bit.ly/3ashYGV.
Approvals in 2020
Pembrolizumab (Keytruda) was approved for a range of new indications last year, including:Avelumab (Bavencio) was approved for maintenance therapy in patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy. https://bit.ly/3ar8XOs.
Nivolumab (Opdivo) was approved for:
Patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma after prior fluoropyrimidine- and platinum-based chemotherapy. https://bit.ly/3ar4bjX. Use in combination with ipilimumab as first-line treatment in adults with unresectable malignant pleural mesothelioma. https://bit.ly/2NbQ60V.Atezolizumab (Tecentriq) was approved in combination with cobimetinib and vemurafenib for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. https://bit.ly/2NzkodG.
Osimertinib (Tagrisso) was approved for adjuvant therapy after tumor resection in patients with non–small cell lung cancer whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. https://bit.ly/2NC0aQs.Selinexor (Xpovio) was approved for:
Use in combination with bortezomib and dexamethasone for the treatment of adults with multiple myeloma who have received at least one prior therapy. https://bit.ly/3s1u1kp. Adults with relapsed or refractory diffuse large B-cell lymphoma not otherwise specified, including disease arising from follicular lymphoma, after at least two lines of systemic therapy. https://bit.ly/2M172GW.The FDA also approved a new fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) for subcutaneous injection for:
Use in combination with chemotherapy as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. Use in combination with chemotherapy as adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence. Use in combination with docetaxel to treat patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. https://bit.ly/2LXA4XX.Relugolix (Orgovyx) was the first oral gonadotropin-releasing hormone receptor antagonist approved by the FDA for adults with advanced prostate cancer. https://bit.ly/3qyJisQ.
Approvals in 2021
Cemiplimab-rwlc (Libtayo) was approved for patients with locally advanced or metastatic basal cell carcinoma previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate. https://bit.ly/3ppkW31.
Daratumumab plus hyaluronidase (Darzalex Faspro) was approved in combination with bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed light chain amyloidosis. https://bit.ly/3bbaF5I.
Approval in 2019
In late 2019, the FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu) for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. https://bit.ly/3qw9tA4.
Show notes written by Sheila DeYoung, DO, a resident at Pennsylvania Hospital, Philadelphia.
Disclosures
Dr. Mintzer and Dr. Henry have no relevant disclosures.
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The NCI-MATCH trial was designed to reveal mutations in underexplored cancer types, allowing researchers to match patients to appropriate targeted therapies.
Study investigator Alice P. Chen, MD, from the National Cancer Institute, reviews the goals and results of NCI-MATCH with host David H. Henry, MD, in this episode.
Trial details
NCI-MATCH has more than 1,000 participating sites. The trial is open to patients with advanced cancers that have progressed on standard treatment or rare cancers for which there is no standard treatment. Investigators use next-generation sequencing to identify mutations in tumor biopsies taken before the start of therapy. Sequencing is performed at MD Anderson Cancer Center, Houston; Massachusetts General Hospital, Boston; MoCha at NCI’s Frederick (Md.) National Lab; Yale University, New Haven, Conn.; and commercial labs.Matching patients to treatment
When a patient is found to have an actionable mutation, that patient is assigned to an investigational treatment, typically monotherapy. A patient cannot be assigned to a treatment that is already known to be effective against their cancer; for example, patients with BRAF-mutated melanoma were excluded. The NCI’s Cancer Therapy Evaluation Program sends the patient's targeted therapy to the participating site within 24 hours of notification. CT imaging is done prior to the start of treatment, and patients are monitored with repeat scans every two cycles.Results
Data on 5,954 patients with refractory malignancies were recently reported (J Clin Oncol. 2020 Nov 20;38[33]:3883-94). About 38% of those patients had an actionable mutation, and about 18% were assigned to a targeted therapy. Reports have shown varying response rates to matched therapy, ranging from 2% to 38%, Dr. Chen said. Results from the trial's treatment arms can be found here: https://ecog-acrin.org/nci-match-eay131-findings. Dr. Chen noted that this trial was designed to match patients with single agents. Combination therapy has only been used in one arm of the study (J Clin Oncol. 2020 Aug 06. doi: 10.1200/JCO.20.00762).Future directions
Nine treatment arms are still open, and one arm has yet to open. Conclusions are still pending the completion of the treatment arms. The next step for this research is expanding to include more combination therapies. There is also interest in comparing biopsies of tissue obtained at initial diagnosis and after treatment to further improve understanding of mutations. For more information on NCI-MATCH, visit: https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match. https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCT02465060.Show notes written by Sheila DeYoung, DO, a resident at Pennsylvania Hospital, Philadelphia.
Disclosures
Dr. Chen and Dr. Henry have no conflicts of interest.
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How do the various COVID-19 vaccines work, and when should patients be vaccinated? We tackle these topics and more in this episode.
Testing of mRNA vaccines began in the 1990s. An initial problem with these vaccines was that the RNA was highly inflammatory. Dr. Weissman and his colleague, Katalin Karikó, PhD, discovered how to fix that problem in 2005. The pair found that placing modified nucleosides into mRNA made it noninflammatory and allowed for increased production of protein from the RNA – up to a 1,000-fold increase in mice. This technology is the basis of the Moderna and Pfizer/BioNTech COVID-19 vaccines.
Our host David H. Henry, MD, is joined by Drew Weissman, MD, PhD, a professor at the University of Pennsylvania, Philadelphia. Dr. Weissman codeveloped the messenger RNA (mRNA) technology being used in the COVID-19 vaccines produced by Pfizer/BioNTech and Moderna.
History of mRNA vaccinesImmunology and vaccines
To produce a good immune response, antigen must be present for a long time, though the optimal amount of time is unknown, Dr. Weissman said. The mRNA lipid nanoparticles (LNPs) used in the COVID-19 vaccines make protein for 10-14 days, resulting in a “great” immune response, according to Dr. Weissman. Most vaccines have an adjuvant, or something that stimulates the immune response by inducing TH1 or TH2 responses. The LNP used in the COVID-19 vaccines is an adjuvant that makes a specialized CD4 helper cell that drives antibody production, increases antibody affinity, and matures antibodies to make long-lived plasma cells to allow for long-lived antibody responses. This is the only adjuvant known that induces these type of helper T cells.COVID-19 vaccine reactions
Adverse reactions to COVID-19 vaccination – flu-like symptoms, arm pain, etc. – are caused by the LNP, not the spike protein. Once the LNP is gone, usually within the first 24 hours, symptoms dissipate. The amount of spike protein produced decreases over 14 days. It’s unclear if patients should take NSAIDs to manage symptoms after COVID-19 vaccination, as this hasn’t been tested. However, with influenza vaccination, taking an NSAID will decrease the immune response.Variants and their impact on vaccination
SARS-CoV-2 variants have been reported in Brazil, South Africa, California, and the United Kingdom. Dr. Weissman explained that there are two kinds of variation: when a virus learns how to better infect people and when the virus learns to avoid immune responses. Most SARS-CoV-2 variants are equally addressed by the vaccines, though we know vaccines have reduced efficacy against the South African variant, Dr. Weissman said. The good news is that coronavirus mutates very slowly, and it’s easy with mRNA vaccines to “plug in” a mutant and make a more effective vaccine, Dr. Weissman said.Vaccinating cancer patients: Treatment considerations
We don’t know the best time to administer COVID-19 vaccines to patients on chemotherapy, as this hasn’t been studied, Dr. Weissman said. When other vaccines were given to subjects receiving chemotherapy, those vaccines did not work as well. Chemotherapy knocks down myeloid cells around day 7, with recovery typically around day 28. Dr. Weissman said he would probably vaccinate at day 14 in the chemotherapy cycle, as the germinal centers where B cells are produced form about 2-7 days after receipt of the vaccine.
For patients receiving chemotherapy:For patients receiving checkpoint inhibitors:
The optimal time for vaccination in patients receiving checkpoint inhibitors is unknown. However, the immune response to vaccination in patients on checkpoint inhibitors is expected to be similar to the general population or slightly enhanced.For patients receiving anti-CD20 antibodies:
Anti-CD20 antibodies might blunt the B-cell response to vaccination. Rituximab, for example, depletes B cells in the circulation for months. In the absence of B cells, there won’t be a good antibody response. T-cell response is also stimulated by COVID-19 vaccines, but we don’t know how effective that response will be in protecting against infection, Dr. Weissman said.Vaccinating HIV patients
Patients with well-controlled HIV (i.e., low viral load and CD4 counts >200) should generate a good immune response, Dr. Weissman said. Patients with poorly controlled HIV (i.e., high viral loads and low CD4 counts) are likely to have a poor immune response to vaccination, though it isn’t clear how poor the response will be.Should patients who recently had COVID-19 get vaccinated?
Clinicians are waiting 90 days to vaccinate patients who have a positive COVID-19 test, Dr. Weissman said. In 95% of cases, SARS-CoV-2 infection conveys protective antibodies for at least 3 months. Patients with recent SARS-CoV-2 infection have more severe adverse reactions to vaccination (e.g., fever, arm pain, flu-like symptoms). It’s safe to wait until 2 weeks after recovery from infection before receiving the vaccine, and vaccination is expected to work well with a boosted immune response, Dr. Weissman said.Is there any role for checking antibody status after vaccination?
Phase 3 trials of the Pfizer/BioNTech and Moderna vaccines showed that levels of neutralizing antibodies were higher in vaccinated patients than in those who had recently been infected; i.e., vaccines give a better immune response than infection. The durability of response to the vaccines is unknown, but studies are underway. The challenge for clinicians is that the antibody assays available are not directed at the spike protein, and they are not quantitative.Vaccine on the horizon
The COVID-19 vaccine under development by Johnson & Johnson uses adenovirus. The spike protein is inserted into the genome of the adenovirus, and the virus is altered so it cannot replicate, thus preventing its spread. The live virus stimulates the cells to make a better immune response. This type of vaccine is potent and produces lower antigen levels than mRNA vaccines but with better T-cell responses, Dr. Weissman said. On Jan. 29, Johnson & Johnson released phase 3 data for this vaccine (https://bit.ly/3oNXX1k). The vaccine was reported to be 85% effective overall in preventing severe COVID-19.Show notes written by Sheila DeYoung, DO, a resident at Pennsylvania Hospital, Philadelphia.
Disclosures
Dr. Weissman disclosed royalties from Moderna and Pfizer/BioNTech. Dr. Henry has no disclosures.
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The greatest barrier to clinical trial enrollment is patients not knowing an appropriate trial exists, according to a survey of gynecologic cancer survivors.
The medical team never discussed trial participation (50.4%) The patient didn’t qualify for a trial (14.4%) The trial location was too far away (7.2%) The desired trial wasn’t available (4.0%) Insurance didn’t cover trial participation (1.6%) The patient didn’t want to receive a placebo (11.2%), wasn’t interested in experimental therapies (3.2%), didn’t want to be randomized (2.4%), or didn’t trust the medical system (1.6%) Other reason (fill in the blank; 38.4%).
The most common reason survey respondents gave for not enrolling in clinical trials was that their medical team didn't tell them about any trials.
Annie Ellis and Mary (Dicey) Jackson Scroggins – who are both patient advocates and ovarian cancer survivors – conducted this survey and presented the results at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer last year (https://bit.ly/3plI1Vg).
Ms. Ellis discussed the survey results and other related research with host David H. Henry, MD, in this episode.
Ms. Ellis and Ms. Scroggins distributed their 26-question survey online. The survey was completed by 189 survivors of gynecologic cancers.
Most respondents (65.6%) had never participated in a clinical trial. Reasons for nonparticipation included:Roughly a third of respondents (34.4%) had participated in a clinical trial.
Most of these respondents (86.2%) learned about the trial from their doctor. All past trial participants said they would participate again (84.6%) or they were not sure about future participation (15.4%).Ms. Ellis also mentioned a recent review and meta-analysis, which showed that more than half of all cancer patients offered a clinical trial do participate (J Natl Cancer Inst. 2020 Oct 6. doi: 10.1093/jnci/djaa155. https://bit.ly/2Yg4dnP).
Together, these finding suggests cancer patients may be willing to participate in trials but often don’t know that relevant trials exist.
Ms. Ellis noted that her colleague, Ms. Scroggins, often says, “Patients can't go to the party if they don't get an invitation.”
DisclosuresMs. Ellis, Ms. Scroggins, and Dr. Henry have no conflicts of interest.
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New studies have shed additional light on how convalescent plasma may affect patients with COVID-19, how blood type impacts bleeding risk, the effects of race on cancer-associated thrombosis, and iron deficiency in pregnancy.
These studies were presented as part of the “Best of ASH” session at the 2020 annual meeting of the American Society of Hematology.
Alisa S. Wolberg, PhD, of the University of North Carolina at Chapel Hill, who cochaired the session, reviews these studies with host David H. Henry, MD, in this episode.
Abstract #572: Association of ABO Blood Group with Bleeding Severity in Patients with Bleeding of Unknown Cause. https://bit.ly/2Mc0R2A.
This study, which included 422 patients, indicated that blood group O is overrepresented in patients with bleeding of unknown cause. Blood group O was associated with a more severe bleeding phenotype, especially oral mucosal bleeding, independent of the levels of von Willebrand factor and factor VIII. Patients with blood group O had increased clot density, but blood group O didn’t influence thrombin generation or platelet function analysis. The researchers said these findings are important for better understanding the underlying mechanisms of bleeding in patients who have bleeding of unknown cause. Dr. Wolberg said this study reframed how people look at bleeding of unknown cause.Abstract #203: Racial/Ethnic Disparities in Cancer-Associated Thrombosis: A Population-Based Study. https://bit.ly/35Xi5HE.
This study included more than 942,109 cancer patients. Results showed an independent association between race/ethnicity and the risk of cancer-associated thrombosis. Asians/Pacific Islanders had a significantly lower incidence of cancer-associated thrombosis, compared with non-Hispanic Whites. African Americans had a significantly higher incidence of cancer-associated thrombosis versus non-Hispanic Whites. Racial/ethnic differences were especially prominent when examining pulmonary embolism only. It’s hard to determine what causes these differences, Dr. Wolberg said. The differences could be explained by underlying biological traits, systemic racism, access to care, and/or the severity of underlying comorbidities, according to the researchers.Abstract #424: Suboptimal Iron Deficiency Screening in Pregnancy in a High Resource Setting. https://bit.ly/2XYedSA.
The study included data on 47,590 pregnancies in 44,552 women from Ontario. About 40% of these patients (n = 25,880) had ferritin measurements taken during pregnancy. Iron deficiency was observed in 52.8% of evaluable pregnancies, and severe iron deficiency was seen in 23.8%. These findings suggest a ferritin test should be included as part of routine bloodwork at the first prenatal visit, the researchers said. They also noted that failing to evaluate iron stores in the second and/or third trimester misses the periods of highest iron-deficiency risk, when intravenous iron may be considered. The researchers said these gaps in care should be addressed by revising guidelines.
For this study, researchers compared 15 cases and 30 controls, all of whom had COVID-19. Cases received two units of COVID-19 convalescent plasma (CCP) from different donors. CCP appeared to improve survival in hospitalized COVID patients, though the difference was not significant. The 28-day mortality rate was 6.7% among cases and 20.7% in controls (P = .233). The researchers also found that unselected CCPs have heterogeneous antivirus activity. Pathogen reduction treatment did not impact antivirus activity. ADAP, ACE2, RVPN, and COVAM could be used to define activity. A posttransfusion increase in activity could be detected in some, but not all, patients. The researchers said more definitive studies are needed.
Abstract #245: Efficacy of COVID-19 Pathogen-Inactivated Convalescent Plasma for Patients with Moderate-to-Severe Acute COVID-19: A Case-Matched Control Study. https://bit.ly/2XVlulU.
*Some of the data presented at the meeting differ from data included in the abstracts.
Disclosures:Dr. Wolberg disclosed relationships with Bristol-Myers Squibb, GlaxoSmithKline, and Takeda. Dr. Henry has no financial disclosures relevant to this episode.
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Three studies revealed new findings on thrombosis in patients with cancer and/or COVID-19. These studies were presented at the 2020 annual meeting of the American Society of Hematology.
One study suggested the Khorana score may be ineffective for predicting venous thromboembolism (VTE) in cancer patients. Another study revealed factors that can predict VTE in patients with cancer and COVID-19. And a third study indicated that antithrombotic agents don’t improve outcomes in patients with severe COVID-19.
Kristen M. Sanfilippo, MD, of Washington University, St. Louis, reviews these studies with host David H. Henry, MD, in this episode.
Abstract 202: Performance of Khorana Score to Predict One-Year Risk of Venous Thromboembolism in Over Two Million Patients With Cancer. https://bit.ly/3oCHOfQ.
The study included 2,112,260 patients with cancer. At 1 year after diagnosis, 227,170 (10.8%) patients had developed VTE. The Khorana score was a weak to modest predictor of the 1-year risk of VTE (area under the curve, 0.565; 95% confidence interval, 0.564-0.566).Abstract 204: Incidence of and Risk Factors for Venous Thromboembolism Among Hospitalized Patients With Cancer and COVID-19: Report From the COVID-19 and Cancer Consortium (CCC19) Registry. https://bit.ly/38waPnX.
The study included 1,813 hospitalized patients with COVID-19 and cancer who were enrolled in the CCC19 registry. Patients had an increased risk of VTE if they had received anticancer therapy in the last 3 months (odds ratio, 1.63), had active disease (OR, 1.25 for stable/responding disease and 1.67 for progressing disease), had a cancer subtype with a high VTE risk (OR, 1.57 for high risk and 3.42 for very high risk), or were admitted to the ICU within 48 hours of hospitalization (OR, 2.38). Patients had a reduced risk of VTE if they received preadmission anticoagulant (OR, 0.80) or antiplatelet therapy (OR, 0.71). The researchers said this information will aid the development of a risk prediction tool for VTE in hospitalized patients with cancer and COVID-19. For more information on the CCC19 registry, listen to the Blood & Cancer episode, “Studying cancer patients with COVID-19: NCCAPS and CCC19.” https://bit.ly/39lB0x0.Abstract 206: Anticoagulant and Antiplatelet Use not Associated With Improvement in Severe Outcomes in COVID-19 Patients. https://bit.ly/3bvHqvV.
This retrospective study included 28,076 patients with confirmed COVID-19 – 1,024 of whom were on antiplatelet agents, anticoagulants, or both. Chronic anticoagulant or antiplatelet use was not associated with a significantly lower risk of VTE (OR, 1.44), emergency department visit (OR, 0.94), ICU stay (OR, 0.87), or death (OR, 0.91). However, anticoagulant or antiplatelet use was associated with a decreased risk of ventilator use (OR, 0.72). Overall, these findings suggest chronic anticoagulant or antiplatelet use don't mitigate disease severity in COVID-19 patients, the researchers concluded.The session in which these abstracts were presented is entitled, “904. Outcomes Research – Non-Malignant Conditions: Venous Thromboembolism Associated With Cancer and/or COVID-19,” and details can be found here: https://bit.ly/39olwIl.
Data in some of the abstracts differ from data presented at the meeting.
Disclosures
Dr. Sanfilippo disclosed relationships with Covington & Burling, Luther & Associates, Bayer, Health Services Advisory Group, and Amgen. Dr. Henry has no relevant disclosures.
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David Henry on Twitter: @davidhenrymd
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