A coalition of professional organizations issued a joint statement on Monday imploring health care employers to require COVID-19 vaccinations for their employees. More than 50 professional health care organizations signed the statement, including the American Society of Hematology (ASH), the American Society of Clinical Oncology, the American Society for Radiation Oncology, the Society for Gynecologic Oncology, and the American Medical Association.

The groups said their endorsement of mandatory COVID-19 vaccination “aims to protect the safety of patients and residents of long-term care facilities,” according to a news release issued by ASH. They hope to establish the health care sector a leader in COVID-19 vaccination.

If implemented, this mandate would cover 17 million health care workers.

“Health care workers have an ethical duty to put patients’ health and well-being first. and getting vaccinated for COVID-19 is integral to that duty,” Ezekiel J. Emanuel, MD, PhD, said in a statement, which he organized. Emanuel is vice provost for global initiatives at the University of Pennsylvania. He is also a breast oncologist, the Diane v.S. Levy and Robert M. Levy University Professor at University of Pennsylvania and co-director of the school’s Health Transformation Institute. He formerly served as special advisor for health policy to the director of the Office of Management and Budget in the White House for the Obama Administration and chair of the Department of Bioethics at the National Institutes of Health for 14 years.

“Employer vaccine mandates are effective and lifesaving, and they are especially appropriate in health care and long-term care settings,” Emanuel added. “No patient should have to worry that they could become infected by one of their care providers, and no provider should put their patient at risk.”

The statement comes as COVID-19 diagnoses, hospitalizations, and deaths are on the rise, mostly among the unvaccinated. Health care workers are more likely to be fully vaccinated than the general population. However, approximately one-quarter of hospital workers who have direct contact with patients had not received a single dose of a COVID-19 vaccine as of the end of May 2021, according to a WebMD and Medscape Medical News analysis of data collected by the Department of Health and Human Services from 2500 hospitals across the United States.

Vaccine administration peaked in late March and early April. The spread of the delta variant, which is more contagious than the alpha variant and resistant to vaccination, has also given new life to a pandemic that seemed to be winding down.

“As the number of cases, hospitalizations and deaths continue to rise due to the COVID-19 delta variant, especially among unvaccinated persons, requiring that all health care workers who can get vaccinated receive a COVID-19 vaccine will help protect them, their patients, loved ones and others who are vulnerable and immunocompromised,” George M. Abraham, MD, MPH, president of the American College of Physicians, said in the statement.

CDC director Rochelle Walensky, MD, has said that as many as 99% of COVID-19 deaths over the past 6 months have been among those who are unvaccinated.

The Alabama Department of Public Health issued a report July 13 saying that the state had recorded 529 COVID-19 deaths since April 1.

 Of those, 509 were unvaccinated. As of July 16, only 33.6% of the state’s total population and 42.3% of the adult population was fully vaccinated.

The Johns Hopkins Coronavirus Resource Center has recorded 20,733 new cases and 147 new deaths in Alabama over the past 30 days.

In contrast, Vermont leads the nation with more than 68% of the total population fully vaccinated. There have been 3 COVID-19 deaths over the past 30 days, down from a high of 67 in December 2020.

Major health care professional organizations call for covid-19 vaccine mandates for all health workers. News release. July 26, 2021. Accessed July 26, 2021. https://bit.ly/3BFUHwJ

Goodman B, Miller A. Huge number of hospital workers still unvaccinated. WebMD Health News. June 28, 2021. Accessed July 26, 2021. https://wb.md/2UIjOi1

Lopez Bernal J, Andrews N, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant. 

. Published online ahead of print July 21, 2021. doi:10.1056/NEJMoa2108891

Alabama Public Health. Unvaccinated people represent 96.2 percent of COVID-19 deaths in Alabama since April 1. July 13, 2021. Accessed July 26, 2021. https://bit.ly/3iOsrPN

US Department of Health and Human Services. COVID-19 Community Profile Report. Alabama state synopsis. July 16, 2021. Accessed July 26, 2021. https://bit.ly/376WBs0

Johns Hopkins University of Medicine Coronavirus Resource Center. Alabama. Accessed July 26, 2021. https://bit.ly/3BTsUZY

Johns Hopkins University of Medicine Coronavirus Resource Center. Vermont. Accessed July 26, 2021. https://bit.ly/3f0yGip

This article was originally published on OncLive as 

“Cancer Organizations Call for Mandated COVID-19 Vaccines for Health Care Workers”

Articles

Several cancer organizations signed a group statement calling for health care employers to mandate COVID-19 vaccinations for their employees.  

Cancer Organizations Implore Health Care Employers to Mandate COVID-19 Vaccines 

Post-treatment care for breast cancer survivors must be personalized to address each survivor’s unique experiences, according to a study presented at the ESMO Breast Cancer Virtual Congress 2021. Women in the low- and intermediate-burden subgroups had symptom scores better or equal to the average Dutch woman but many in the high-burden subgroup were significantly worse than average for all 11 symptoms evaluated.

The low subgroup reported a lower symptom burden compared to the general population. The intermediate subgroup experienced burden similar to the general population, although scores for fatigue, insomnia, and cognitive symptoms were slightly worse.

Symptom burden in the high subgroup was significantly than the general population. Compared with the intermediate subgroup, patients in the high burden group were more likely to have at least 1 comorbidity (relative risk ratio (RRR), 2.75; 95% CI, 1.22-6.19; 

 = .015) and more likely to have multiple comorbidities (RRR, 9.19; 95% CI; 3.70-22.8; 

“I was pleasantly surprised to find that so many survivors were doing as well or even better than the average Dutch woman,” lead author Kelly de Ligt, PhD, from the Netherlands Cancer Institute in Amsterdam, said in a news release.

de Ligt added that the findings in the high-burden subgroup were alarming. “This was the smallest group, only 15% of our population, but nonetheless, 1 in 6 women in our study had worse scores than the general population for all symptoms. The differences, ranging between 15 and 20 percentage points, were large enough to be considered not just statistically significant, but clinically relevant as well.”

More and more women are living longer following a diagnosis of breast cancer. The 10-year survival rate is greater than 70% in Europe and 84% for non-metastatic invasive disease in the United States.

 Quality of life is extremely important for these patients and de Ligt said these findings confirm the necessity for personalized approaches to the follow-up of cancer patients, some of whom still require special attention as long as 5 years after diagnosis.

de Ligt and her colleagues surveyed 404 women who received surgery with or without adjuvant treatment for stage I to III breast cancer selected from the Netherlands Cancer Registry. Participants were 1 to 5 years postdiagnosis and compared with a representative sample of 1300 women from the general population.

Investigators assessed participants for fatigue, nausea, pain, dyspnea, insomnia, appetite, constipation, diarrhea, financial burden, and emotional and cognitive symptoms on a scale 0-100 through the EORTC-QLQ-C30. Participants were then segregated into low- (28.7%), intermediate- (55.4%), and high-burden groups (14.6%) based on their responses.

de Ligt and her team also determined that patients with comorbidities such as heart disease and diabetes were more likely to experience a high symptom burden. de Ligt said the association was so strong that investigators could not connect the level of symptom burden with the type of therapy received.

“Future research should attempt to measure patients’ health-related quality of life through Patient Reported Outcome Measures (PROMs) before the start of treatment for breast cancer and afterwards to allow us to measure the effect of the therapy,” she said.

de Light KM, de Rooij BH, Walraven I, et al. Towards tailored follow-up care for breast cancer survivors: cluster analyses based on symptom burden. Presented at: ESMO Breast Cancer Virtual Congress 2021. Abst # 134P_PR. 

Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow up. 

Breast cancer: statistics. Cancer.net. January 2021. Accessed May 4, 2021. https://www.cancer.net/cancer-types/breast-cancer/statistics

This article was originally published on OncLive as, "

Breast Cancer Survivors Need More Tailored Follow-Up Care

Each patient with breast cancer has a unique experience. Their survivorship care should reflect that.

Tailored Survivorship Care Is Needed in the Breast Cancer Space

PARP inhibitors and novel combinations targeting the androgen receptor (AR) will help define the future treatment paradigm for patients with metastatic castration-resistant prostate cancer (mCRPC), according to William Kevin Kelly, DO.

Investigators have identified molecular changes that occur when a patient’s disease progresses from a castration-sensitive state to a castration-resistant state, which has helped drive advances in therapeutic options, Kelly said in a presentation during the New York GU™ 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies conference.

“This gave opportunities for investigators to look at these pathways and develop new targets for these alterations,” said Kelly, a professor of medical oncology and urology at Thomas Jefferson University and director of the Division of the Solid Tumor Oncology at Sidney Kimmel Cancer Center at Jefferson Health, both in Philadelphia.

Study findings have shown that the frequency of DNA repair alterations increases as prostate cancer progresses; an estimated 19% to 23% of patients with mCRPC harbor mutations in this pathway, Kelly said.

PARP inhibitors, which target aberrant DNA repair mechanisms, entered the treatment landscape for last year when the FDA approved 2 agents for patients with mCRPC within less than a week.

 On May 15, 2020, rucaparib (Rubraca) became the first biomarker-driven targeted therapy for the malignancy when the FDA granted an accelerated approval for its use in patients with 

-mutant mCRPC (germline and/or somatic) who received prior AR-directed therapy and taxane-based chemotherapy.

Rucaparib was approved based on findings from the single-arm phase 2 TRITON2 trial (NCT02952534), in which monotherapy with the PARP inhibitor resulted in a confirmed objective response rate (ORR) of 43.5% (95% CI, 31.0%-56.7%) by independent review, with 7 (11.3%) complete responses and 20 (32.3%) partial responses. The confirmed ORR by investigator assessment was 50.8% (95% CI, 38.1%-63.4%).

Final approval for rucaparib is contingent on the results of the phase 3 TRITON3 trial (NCT02975934), which is seeking to recruit 400 patients with mCRPC harboring a 

 mutation that has progressed after 1 prior line of therapy with a next-generation AR-targeting therapy.

Four days after rucaparib was approved, olaparib (Lynparza) gained a new indication for treating patients with deleterious or suspected deleterious germline or somatic mutations in homologous recombination repair (HRR) genes including 

 who have progressed following treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga) based on findings from the phase 3 PROfound trial (NCT02987543).

In PROfound, investigators determined that olaparib monotherapy was superior to prednisone plus either enzalutamide or abiraterone for patients with mCRPC who had tumors with at least 1 alteration in 

 (cohort A) or in any of 12 HRR genes (cohort B). The study population included 387 patients who had disease progression on prior hormone-targeting agents.

In cohort A, the median radiological progression-free survival (rPFS), the primary endpoint of the study, was 7.4 months (95% CI, 6.2-9.3) for those who received olaparib vs 3.6 months (95% CI, 1.9-3.7) for those who had physician’s choice of standard therapy, which translated into a 66% reduction in the risk of disease progression or death (HR, 0.34; 95% CI, 0.25-0.47; 

 <.0001). In cohort A plus B, median rPFS was 5.8 months for olaparib (95% CI, 5.5-7.4) vs 3.5 months (95% CI, 2.2-3.7), resulting in an HR of 0.49 (95% CI, 0.38-0.63; 

Olaparib also demonstrated an improvement in median OS. In cohort A, the median OS was 19.1 months (95% CI, 17.4-23.4) with olaparib vs 14.7 months (95%CI, 11.9-18.8) for physician’s choice of therapy (HR, 0.69; 0.50-0.97; 

 = .02). In cohorts A plus B, the median OS was 17.3 months (95% CI, 15.5-18.6) vs 14.0 months (95% CI, 11.5-17.1), translating into an HR of 0.79 (95% CI, 0.51-1.03).

Kelly added that new data presented at the 2021 Genitourinary Cancers Symposium showed that patients with 

 mutations also exhibit significant response to olaparib.6 “Those are another subset of patients that we need to understand and possibly treat in the future,” he said.

In addition to PARP inhibitor studies, the treatment landscape is being shaped by trials that explore therapies in combination or in sequence. “Therapeutic options for mCRPC have greatly expanded over the years,” Kelly said. “So, really, the question is, What comes next? How do we actually pick the order [of treatments]? Or are there better combinations?”

Of note, the efficacy of cabazitaxel (Jevtana), a taxane chemotherapy, was established in the setting of recurrent mCRPC in the phase 4 CARD trial (NCT02485691) in patients who had previously received docetaxel and progressed within 1 year of receiving either enzalutamide or abiraterone. Participants were randomized to receive cabazitaxel plus prednisone and granulocyte colony-stimulating factor vs abiraterone plus prednisone or enzalutamide.

Patients who received cabazitaxel had a median imaging-based progression-free survival of 8.0 months (95% CI, 5.7-9.2) vs 3.7 months (95% CI, 2.8-5.1) for those who received an antiandrogen (HR, 0.54; 95% CI, 0.40-0.73; 

 <.001). The secondary end point of median OS was 13.6 months (95% CI, 11.5-17.5) with cabazitaxel versus 11.0 months (95% CI, 9.2-12.9) with either antiandrogen (HR, 0.64; 95% CI, 0.46-0.89; 

“The quality-of-life measures were better all the way through with cabazitaxel versus another AR-directly therapy,” Kelly added. “Pain response was significantly better with the use of cabazitaxel, 45.0% vs 19.3%. Probability of no pain progression was also improved with chemotherapy vs abiraterone or enzalutamide, which really starts defining that chemotherapy still has a role in patients with mCRPC.”

In the phase 3 ACIS trial (NCT02257736), investigators found that adding apalutamide (Erleada), an AR inhibitor, to abiraterone plus prednisone reduced the risk of radiographic progression or death by 30% in patients with chemotherapy-naïve mCRPC receiving androgen deprivation therapy (ADT).

At a median follow-up of 54.8 months, the median rPFS was 24.0 months in the apalutamide arm compared with 16.6 months with placebo plus abiraterone and prednisone (HR, 0.70; 95% CI, 0.60-0.83). OS in the combination arm was 36.2 versus 33.7 months in the control arm (HR, 0.95; 95% CI, 0.81-1.11; 

The findings met the primary end point of the study, but did not significantly improve OS, Kelly noted. He said subgroup analyses may provide further information about which patients could benefit from the approach.

“There are multiple other opportunities for AR-targeted therapies,” Kelly said. “There's multiple new agents that are going to be reporting out that look at different targets from EZH2 to BET inhibitors to transcription coactivators such as CBP and p300, inhibitors that are unique actions and we look forward to those trials coming out.”

Kelly WK. New approaches for advanced CRPC: hormonal agents and PARP inhibitors. Presented at: New York GU™ 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 12-13, 2021; Virtual.

Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated March 10, 2021. Accessed March 15, 2021. 

Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. 

. 2020;38(32):3763-3772. doi:10.1200/JCO.20.01035

Lynparza. Prescribing information. AstraZeneca; 2020. Accessed March 15, 2021.

Hussain M, Mateo J, Fizazi K, et al; PROfound Trial Investigators. 

. 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485

De Bono JS, Matsubara N, Penel N, et al. Exploratory gene-by-gene analysis of olaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): PROfound. 

. 2021;39(suppl 6):126. doi:10.1200/JCO.2021.39.6_suppl.126

de Wit R, de Bono J, Sternberg, CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. 

. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206

Rathkopf DE, Efstathiou E, Attard G, et al; ACIS investigators. Final results from ACIS, a randomized, placebo (PBO)-controlled double-blind phase 3 study of apalutamide (APA) and abiraterone acetate plus prednisone (AAP) versus AAP in patients (pts) with chemo-naive metastatic castration-resistant prostate cancer (mCRPC). 

. 2021;39(suppl 6):9. doi:10.1200/JCO.2021.39.6_suppl.9

This article originally appeared on OncLive as, "

PARP Inhibitors, Novel Combos Represent the Future in Metastatic CRPC

PARP inhibitors and novel combinations targeting the androgen receptor will help define the future treatment paradigm for patients with metastatic castration-resistant prostate cancer.

What's Next in mCRPC Treatment? Expert Weighs In

Treatment with chimeric antigen receptor (CAR) T cells has induced unprecedented overall response rates (ORR) and complete response (CR) rates in patients with relapsed/refractory B cell malignancies. However, up to 50% of patients will relapse.1

 International Congress on Hematologic Malignancies, David B. Miklos, MD, PhD, associate professor of medicine (blood and marrow transplantation) at the Stanford University Medical Center, suggested that CAR agents targeting multiple antigens might hold the key to breaking through that resistance.

Previous studies have established several factors associated with relapse following CAR T therapy, including loss of the CD19 antigen and aberration in the CD58 antigen, which helps to activate engineered T cells and assists in killing cancer cells.

In a presentation at the 2018 American Society of Hematology Annual Meeting, Jean Oak, PhD, and colleagues found that 8 of 22 (36%) of patients with refractory B cell lymphomas who did not respond to treatment with axicabtagene ciloleucel (Axi-cel) or relapsed after day 28. Five patients (62%) who failed therapy had loss or downregulation of CD19, suggesting that single target antigen loss is a common mechanism of CAR T failure.2

Majzner et al analyzed CD58 status in 51 patients who were treated with axicabtagene ciloleucel for relapsed/refractory B cell lymphomas. Twelve (24%) patients had CD58 mutation or lack of expression, and 11 of those 12 had progressive disease.3

Studies have found CD4+ expression is an indication of patient response. For example, Zinaida Good, PhD, and her colleagues conducted a study seeking to identify cell features distinguishing patients with diffuse large B cell lymphoma (DLBCL) who had durable complete response (CR) at 6 months following axicabtagene ciloleucel treatment from those who had progressive disease. They found that the presence of CD4+ cells on day 7 was highly associated with clinical outcome at 6 months.4

At Stanford, investigators have been experimenting with a bispecific bivalent, single polypeptide called a “loop CAR” over the past 4 years to overcome antigen loss. Miklos showed data from a phase 1 dose escalation study of a bispecific anti CD19/CD22 using a self-contained prodigy production system to generate CAR T cells for patients with acute lymphoblastic leukemia (ALL; n = 17), primary mediastinal B-cell lymphoma (PMBCL; n = 2), and DLBCL (n = 20).

“We had day 28 overall response rates in patients with ALL of 100% and we had complete response of 88%,” Miklos said. “The Kaplan-Meier curve shows that the lymphoma fall off after 6 months was somewhere around 50%, but in truth it’s 29%. In truth, we don't think that the lymphoma responses are competitive with the commercially available products.”

Furthermore, 36% of patients with DLBCL or PMBCL and 50% of those with ALL have relapsed. Stanford, and other groups, will reapproach multi-antigen targeting with new constructs and strategies, Miklos said. There is still an unmet need for a commercially available therapy for adults with relapsed/refractory ALL.

Other investigators, however, are have some success. Nirav N. Shah, MD, and colleagues administered bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed/refractory B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia. Eighteen of 22 patients (82%) had an overall response at day 28 with a CR rate of 64%.5 This was a phase 1 dose escalation and expansion trial that to evaluate safety, as well as the feasibility of on-site manufacturing using the CliniMACS Prodigy system.

Cai Q, Zhang M, Li Z. Potential strategies against resistance to CAR T-cell therapy in haematological malignancies. 

Oak J, Spiegel JY, Sahaf B, et al. Target antigen downregulation and other mechanisms of failure after axicabtagene ciloleucel (CAR19) therapy. 

 2018;132(Suppl 1): 4656. doi:10.1182/blood-2018-99-120206

Majzner RG, Frank MJ, Mount C, et al. 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. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020. Abstr 556.

Good Z, Spiegel JY, Sahaf B, et al. Identification of two CAR T-Cell populations associated with complete response or progressive disease in adult lymphoma patients treated with Axi-Cel. 

 2019;134 (Suppl 1):779. doi:10.1182/blood-2019-130815

Shah, NN, Johnson, BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. 

.2020;1569–1575. doi:10.1038/s41591-020-1081-3

Multi-Agent Therapy May Overcome CAR T Resistance in B Cell Malignancies

Up to 50% of patients with B-cell malignancies will relapse on CAR T-cell therapy. Investigators are looking in to new ways to overcome that drug resistance.

Overcoming CAR T Resistance in B-Cell Malignancies

By and large, the patients treated at Mount Sinai Health System during the early days of the coronavirus disease 2019 (COVID-19) pandemic were not dying of the virus, according to Miriam Merad, MD, PhD. In fact, autopsies showed that patients were dying despite clearing the virus.

Investigators did not see a correlation between death and viral load or disease severity. Rather, data from these patients showed that as patients got sicker, they developed a severe inflammatory response.

“The virus was triggering the disease, but it was not really responsible for the organ damage…that we were seeing,” Merad said.

An immunologist and oncologist, Merad has spent her career studying inflammation in patients with cancer and was at the right place at the right time to translate her expertise to examine inflammation in patients with COVID-19. She is the Mount Sinai Endowed Professor in Cancer Immunology and director of the Precision Immunology Institute at Ichan School of Medicine at Mount Sinai in New York, New York. She is also the coleader of the Cancer Immunology Program at The Tisch Cancer Institute and director of the Human Immune Monitoring Center (HIMC) at Ichan School of Medicine.

“What we realized was that in those [patients with COVID-19] who were getting worse, they had a very severe inflammatory response,” she said. “I discovered the subset of macrophages that is now helping us understand their contribution to disease better.”

Merad has spent decades investigating macrophages and dendritic cells, which play a critical role in both T-cell activation and T-cell suppression in the context of cancer. Her laboratory has made key discoveries elucidating the mechanisms that control the development and functional identity of dendritic cells and macrophages during homeostasis and understanding how cancer and inflammatory diseases can affect those regulations.

Translating Cancer Research to Critical Practice

Merad and her team, in collaboration with myeloma experts, developed the Ella platform, a rapid cytokine detection system, to measure inflammatory cytokine response to therapy in patients with myeloma.

 When the time came for an all-hands-on-deck approach to address the pandemic, Merad halted her cancer research and dedicated this platform, along with her laboratory, the HIMC, and the Cancer Immunology Program, to assist in treating patients with COVID-19.

Her laboratory adapted that assay to create a test that detects the inflammatory response to COVID-19 and produces a result within 3 hours. The hypothesis is that with these data it will be easier anticipate and block inflammatory surge before the patient sustains organ damage.

“We had all these people trained to study the immune system. I told them that we were going to collect [samples from] all the patients [admitted to] the hospital,” she said. “Because of my understanding of macrophages in the context of different diseases, I was able to potentially help understand why these macrophage cells were being so activated. There are some similarities between cancer and [the virus], so there is definitely knowledge that we have acquired by studying patients with cancer that has been very useful.”

Although the exact drivers of pathologic inflammation are unknown, Merad and colleagues are interested in identifying the pathways involved in the immune response in order to optimize intervention to control the virus and prevent progressive tissue damage that can lead to deleterious hyperinflammation.2

The rapid multiplex cytokine assay was used in patients with COVID-19 admitted to the Mount Sinai Health System between March 21 and April 28, 2020, and measured serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and IL-1β.1 The test was authorized under an emergency use approval from the New York State Department of Health. In an initial cohort of 1484 patients followed up to 41 days post admission, high serum IL-6 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P < .0001 and P = .0140, respectively).

Further, sequential organ failure assessment severity scale scores were available for a subset of 663 patients. Poor survival was associated with IL-6 (HR, 2.9; P < .0001), IL-8 (HR, 1.6; P = .04) and TNF-α (HR, 1.6; P = .03) in these patients.

“Some of these cells are really the biggest producers of inflammatory cytokine,” Merad said. Her hypothesis is that controlling inflammation could help patients survive COVID-19. “The cells are also involved in other types of diseases, especially inflammatory disease, where they are also activated. Therefore, they’re going to activate T cells and contribute to inflammation-driven injury.”

What Lies Ahead for Translational Research

COVID-19 often induces a “cytokine storm,” a severe immune reaction in which the body releases too many cytokines into the blood too quickly. Patients receiving chimeric antigen receptor (CAR) T-cell treatment for leukemia often experience cytokine storm.

Siltuximab (Sylvant) has been used to treat cytokine storm in patients who received CAR T-cell therapy for cancer. Investigators theorize that suppressing IL-6 might be a treatment option for severe COVID-19. In July, the FDA approved a randomized, double-blind, placebo-controlled phase 3 clinical trial comparing intravenous (IV) siltuximab, an anti—IL-6 monoclonal antibody, versus corticosteroids for patients hospitalized with COVID-19–associated acute respiratory distress syndrome.

Investigators are also conducting a clinical trial evaluating sarilumab (Kevzara), a human monoclonal antibody against the IL-6 receptor that is indicated for rheumatoid arthritis, as a potential therapy for COVID-19. The agent is concurrently being investigated in combination with capecitabine for HER2-negative metastatic breast cancer in the phase 1/2 EMPOWER trial (NCT04333706).

Results for sarilumab in COVID-19 have been mixed. In July, drug manufacturers Regeneron Pharmaceuticals and Sanofi stopped a phase 3 US trial evaluating the drug in patients requiring mechanical ventilation after the drug failed to meet primary and secondary end points.3 However, Italian investigators in October concluded that IV sarilumab is an option worth pursuing. In an article published in EClinical Medicine, investigators concluded that sarilumab appeared to be a promising short-term approach for patients with COVID-19—related severe pneumonia.

Merad is less concerned about the clinical results with sarilumab than the biological ones. She is hoping to have that data before the United States faces a second wave of infections.

“I want to see the biological result, what happened to the inflammation, to see whether we are on the right track or not,” she said. “If we are on the right track, this means maybe you have to combine [sarilumab] with other cytokines. So I’m still waiting for Regeneron to release at least some of their biological data.”

Merad said investigators are close to understanding which inflammatory pathways they need to block. The problem now is that trials are moving forward with small patient populations. To her knowledge, investigators were not recruiting any patients in New York.

In a larger sense, New York City pulled together. Merad said local restaurants provided “fantastic food” to her team on a regular basis. High school students sent cards thanking them for their efforts and local schools sent N95 masks. Even her children got involved, baking cakes for investigators.

Some of her team members refused to leave the hospital and Merad had to force them to go home to rest. Others broke down crying from exhaustion. The experience was so intense and the sense of camaraderie so strong that some of her volunteers cried when she released them back to their normal jobs.

At the height of the pandemic in late February and early March, Merad had an “army” of 60 to 80 investigators collecting DNA samples from patients. She and her team worked 12-hour days for weeks on end.

“There was a sense of...facing a war and that we were here together and were fighting together. There was a sense of fighting a war with all members of this community,” she said. “I’ve been here 15 years—I’ve met so many new people, colleagues that I never had the time to meet before.”

Mount Sinai, with locations in Manhattan and Brooklyn, was at the epicenter of the pandemic. At one point, Merad said that the hospital system was seeing 100 new cases of COVID-19 each day, and patients with COVID-19 occupied 6000 beds across the Mount Sinai Health System. Every resource was devoted to battling the pandemic.

“All the scientists were here to help the clinicians come up with clinical strategies because they were overwhelmed. They didn’t know how to treat patients initially—you can’t treat what you don’t understand. So, it was difficult, and the scientists decided that we were going to go full force.

“Science stepped up to the front line. Scientists did it,” she said. “It was an extraordinary time. There was a lot of bleakness and anxiety and sadness and fear. But there was also an extraordinary sense of collaboration and humanity that came out of the bleakness.”

1. Del Valle DM, Kim-Schulze S, Huang HH, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636-1643. doi:10.1038/s41591-020-1051-9

2. EUSA Pharma announces FDA approval of phase 3 clinical trial for siltuximab in hospitalized patients with COVID-19 associated acute respiratory distress syndrome. News release. BioSpace July 2, 2020. Accessed October 26, 2020. https://www.biospace.com/article/releases/eusa-pharma-announces-fda-approval-of-phase-3-clinical-trial-for-siltuximab-in-hospitalized-patients-with-covid-19-associated-acute-respiratory-distress-syndrome/

3. Regeneron and Sanofi provide update on Kevzara (sarilumab) phase 3 U.S. trial in COVID-19 patients. News release. Regeneron Pharmaceuticals. July 2, 2020. Accessed October 20, 2020. https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-update-kevzarar-sarilumab-phase-3

4. Gremese E, Cingolani A, Bosello SL, et al; GEMELLI AGAINST COVID-19 Group. Sarilumab use in severe SARS-CoV-2 pneumonia. EClinicalMedicine. Published online October 2, 2020. doi:10.1016/j.eclinm.2020.100553

Cancer Research May Pave the Way for Treating Severe COVID-19

An immunologist and oncologist, Merad has spent her career studying inflammation in patients with cancer and was at the right place at the right time to translate her expertise to examine inflammation in patients with COVID-19.

Cancer Research May Help Treatment of Severe COVID-19

Maintaining sexual function is often low on the list of priorities for a woman recently diagnosed with a gynecologic cancer, but raising the subject early in her treatment course may make the patient more willing to engage in a discussion as her care progresses, according to Don S. Dizon, MD, who specializes in survivorship issues.

Patients and their partners will remember that the physician initiated the conversation, Dizon said in an interview with 

 is important so that a patient knows there are no limits to what she can talk about with her physician. The physician, he said, leaves the door open until the patient is ready to walk through it.

“It may not be the case that a woman whom you’re asking, ‘Would you like to discuss sexual health at this time?’ is going to go into the extreme details of her intimate sex life, but it might be [the case] months down the road,” said Dizon, director of women’s cancers at Lifespan Cancer Institute, and clinical director of gynecologic medical oncology and director of medical oncology for Rhode Island Hospital, both in Providence.

“When the smog clears from a cancer diagnosis, they may be able to say, ‘You know what? I don’t know how to be intimate with my partner now.’ It’s really important that they understand and recognize that this is a legitimate cause for their concern and that we are here to give them hope,” he said.

Dizon said it can be difficult to discuss this topic with patients, as oncologists often have little or no training in discussing sex and sexual health. Furthermore, physicians may have biases that lead them to assume, for instance, that a woman over 60 years may no longer be interested in sex, or that a lesbian might not be interested in penetrative sex. Dizon added that sex is a “delicate topic,” and the patient may be as unwilling to discuss what she does in the bedroom as the physician is uncomfortable to hear it.

He pointed out, however, that physicians have no trouble discussing with patients the nausea, diarrhea, and vomiting that may result from cancer therapy. “Those are not exactly delicate topics that you’re going to want to bring up in regular conversations,” Dizon said. “And I think, for the same way, we need to start being frank about sexual health and how our treatments would [affect] them. Most of our patients will get better once they have the conversation.”

Dizon advised physicians to develop skills for talking with patients about sexual function and to embrace the topic as a part of routine medical practice. He also encouraged physicians to seek out resources and experts, both externally and within their own institutions, who can help guide patients.

“You need to give patients permission to bring it up,” he said. “We do know from the data that most patients are going to look for cues from their providers that this is a safe area to bring up. They’re not just going to randomly, spontaneously, talk about their sex lives.”

Most advocacy organizations, particularly those that focus on breast cancer, have information available for patients and their loved ones about sexual function issues and restarting their sexual lives after cancer therapy, Dizon said. For adolescent and young adult survivors, the Young Survival Coalition’s Living Beyond Breast Cancer program and Stupid Cancer, in particular, provide information on intimacy and dating.

He also mentioned Will2Love.com, a website for men and women developed by Leslie R. Schover, PhD, whom he described as “one of my mentors” in the field. “It is a self-exploratory website filled with anecdotes and case scenarios, and also information that can empower people to recover, but at their own pace,” Dizon said.

Schover is a clinical psychologist and internationally recognized expert on sexual problems and infertility related to cancer treatment. Dizon serves as a scientific advisor to Will2Love, which works with patients and health care providers to address sexual health concerns and chronic illness.

At Lifespan Cancer Institute, Dizon started the Sexual Health First Responders Clinic to provide personalized, multidisciplinary consultation and treatment for sexual health issues that patients with cancer encounter. The “first responder” aspect of the clinic gives other physicians a place to refer patients who need help.

Dizon also worked with Areej El-Jawahri, MD, a specialist in hematologic malignancies, to develop a sexual health program at Massachusetts General Hospital in Boston for patients who had undergone hematopoietic stem cell transplant. El-Jawahri and colleagues demonstrated that if a pilot program in which patients’ needs were assessed, education was provided, and therapeutic intervention, if appropriate, was offered, this would result in improvements to sexual function, quality of life, and mood.

Nevertheless, Dizon said patients and physicians should not have to depend on having access to in-house expertise for information. Valid information should be available, both online and in the literature, so that people can access the latest data wherever they are, he said.

“Education is exceptionally valuable for anyone who’s having issues related to sexual dysfunction after cancer,” he said. “Having people understand that this is not something they’re going through alone, that a lot of people have issues with sexual health and intimacy and body image after treatment of cancer, makes it feel less isolating as an issue. When people finally get to understand what’s happened and what’s happening, that’s another way to gain control of the situation.”

1. El-Jawahri A, Fishman SR, Vanderklish J, et al. Pilot study of a multimodal intervention to enhance sexual function in hematopoietic stem cell transplantation. Cancer. 2018;124(11):2438-2446. doi:10.1002/cncr.31333

Discussing Sexual Health Early Holds Benefits for Patients With Cancer.

Start Sexual Health Discussions Early On, Says Expert

Ruxolitinib (Jakafi) induced a strong, durable response across several subgroups of patients with steroid-refractory acute graft-versus-host disease (aGVHD), according to data from the REACH2 trial presented at the 25th Annual European Hematology Congress.

In a follow-up analysis to data first published in the New England Journal of Medicine in May 2020, investigators led by Robert Zeiser, MD, University Hospital Freiburg, Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg, Germany, analyzed the effect of treatment on several subgroups of patients.

Zeiser and colleagues found that ruxolitinib improved response in adults aged 18 to 65 (OR, 3.12; 95% CI, 1.84-5.30) and those and those who did not did not respond to or who progressed on high doses of steroids (68.6% vs 32.6%; OR, 5.04; 95% CI 1.85-13.75).

Patients with aGvHD grade II had an ORR of 75.5% with ruxolitinib, the highest response in the study, compared with 50.9% for standard of care (OR 2.96; 95% CI, 1.30-6.76). The ORR for patients with skin involvement was 72.0% versus 47.3% in favor of the experimental arm (OR, 2.99; 95% CI, 1.55-5.79).

Ruxolitinib also induced high response rates in patients with varying degrees of disease severity, organ involvement, related or unrelated donor, and irrespective of prior GVHD therapy used.

The May data showed that overall response rate (ORR) at day 28 was 62.3% with ruxolitinib versus 39.4% with best available therapy (P <.001), in the total population. The durable ORR at 8 weeks, a secondary end point, was 39.6% versus 21.9%, respectively (P <.001). The median failure-free survival was 5 months versus 1 month, respectively (HR, 0.46; 95% CI, 0.35-0.60). The median overall survival was 11.1 months in the ruxolitinib group versus 6.5 months in the control group (HR, 0.83; 95% CI, 0.60-1.15).

The multicenter, open-label, phase 3 REACH2 trial (NCT02913261) randomly assigned 309 patients with steroid-refractory aGVHD to ruxolitinib or investigator’s choice of best available therapy.

Investigators did not detect any new safety signals in this new analysis. In the previous findings, thrombocytopenia, anemia, and cytomegalovirus infection were the most common adverse events (AEs). Does modifications were required in 38% of the ruxolitinib arm and 9% of the control arm. AE-related treatment discontinuation occurred in 11% and 5% of the 2 arms, respectively.

The positive outcomes in REACH2 confirm the findings from the phase 2 REACH1 study, which were the basis of the May 2019 FDA approval of ruxolitinib for the treatment of adult and pediatric patients at least 12 years of age with steroid-refractory acute aGVHD. The study demonstrated that the combination of ruxolitinib with corticosteroids elicited a 57% ORR at day 28 in patients with steroid-refractory aGVHD, with a complete response rate of 31%.

The open-label, single-cohort, multicenter phase 2 REACH1 study accrued patients aged at least12 years old who had received allogeneic hematopoietic stem cell transplantation and developed grade 2 to 4 steroid-refractory aGVHD. Patients had received up to 1 systemic treatment beyond corticosteroids for aGVHD. Of the 71 patients recruited on the trial, 49 patients were refractory to steroids alone, 12 patients had received ≥2 prior anti-GVHD therapies, and 10 patients did not otherwise meet the steroid-refractory definition by the FDA.

The ongoing phase 3 REACH3 trial (NCT03112603) is examining ruxolitinib versus best available therapy in patients with steroid-refractory chronic GVHD after bone marrow transplantation.

Ruxolitinib is also approved by the FDA as a treatment for patients with polycythemia vera who are intolerant of or have an inadequate response to hydroxyurea, as well as for the treatment of patients with intermediate or high-risk myelofibrosis.

1. Zeiser R. Ruxolitinib versus best available therapy in patients with steroid-refractory acute graft-versus-host disease: overall response rate by baseline characteristics in the randomized phase 3 REACH2 trial. Presented at: the 25th European Hematology Congress. June 11-21, 2020. Abstract #S255.

2. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. New Engl J Med. 2020;382:1800-1810. doi:10.1056/NEJMoa1917635

3. FDA approves Jakafi (ruxolitinib) for the treatment of patients with acute graft-versus-host disease. Incyte. Published May 24, 2019. Accessed June 11, 2020. bit.ly/2WiRktX

Ruxolitinib Improves Outcomes in aGVHD Across Subgroups

Ruxolitinib (Jakafi) induced a strong, durable response across several subgroups of patients with steroid-refractory acute graft-versus-host disease.

Ruxolitinib Improves Acute GVHD Outcomes in Some Patients

Treatment with talazoparib (Talzenna) did not demonstrate a statistically significant overall survival (OS) benefit in patients with BRCA1/2-mutated metastatic HER2-negative breast cancer, according to updated findings from the phase 3 EMBRACA trial (NCT01945775).1 However, lead author Jennifer Litton, MD, said that there is still reason to believe treatment with the PARP inhibitor can improve OS.

“In patients with germline BRCA1/2-mutated advanced breast cancer, talazoparib did not [show a] statistically significant improvement in OS compared with chemotherapy,” said Litton, professor of breast medical oncology at The University of Texas MD Anderson Cancer Center, who presented the results during the 2020 AACR Virtual Annual Meeting. “It is important to note that most patients in the study went on to receive subsequent therapies, which may have confounded the survival analysis.”

The FDA approved talazoparib in 2018 for adults with germline BRCA1/2-mutant, HER2-negative locally advanced or metastatic breast cancer based on previously published results from the EMBRACA trial, which showed that the drug was associated with a 3.0-month improvement in median progression-free survival (PFS).

At a median follow-up of 11.2 months, the median PFS was 8.6 months with talazoparib versus 5.6 months (95% CI, 4.2-6.7) with chemotherapy (HR, 0.54; 95% CI, 0.41-0.71; P <.0001). The PFS benefit with talazoparib was seen across all predetermined patient subgroups.

In EMBRACA, patients were assigned to 1 mg daily of oral talazoparib (n = 287) or physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles (n = 144). Eligible patients had received no more than 3 previous cytotoxic regimens for advanced breast cancer, and they had received previous treatment with a taxane, an anthracycline, or both, unless this treatment was contraindicated.

Investigators observed no statistically significant difference in median OS between the talazoparib and chemotherapy arms (19.3 vs 19.5 months, respectively; HR, 0.848; 95% CI, 0.670-1.073; P = .17). The effect of talazoparib was similar regardless of BRCA status.

Investigators performed the final OS analysis using the intent-to-treat population after observing 324 deaths. After a median follow-up of 44.9 months for talazoparib and 36.8 months for chemotherapy, 216 patients in the talazoparib group and 108 patients in the chemotherapy group had died.

Overall, 48.4% of patients in the experimental arm and 59.7% of patients in the control arm went on to receive subsequent treatment with a PARP inhibitor or platinum-based chemotherapy. Of those who received subsequent treatment, 46.3% in the talazoparib group and 41.7% in the chemotherapy group received platinum therapy.

Litton said that adjusting for post-study treatment reduced the hazard ratio and lowered the upper bound of the confidence interval. However, the difference in median OS still did not reach statistical significance compared with chemotherapy in patients who received subsequent PARP inhibitor and/or platinum therapy (19.3 vs 17.4 months, respectively; HR, 0.756; 95% bootstrap CI, 0.503-1.029) or PARP inhibition alone (19.3 vs 19.1 months, respectively; HR, 0.820; 95% bootstrap CI, 0.617-1.047).

“The hazard ratio and 95% confidence intervals obtained for OS after dose adjustment for subsequent platinum and/or PARP inhibition suggest that the primary OS analysis underestimated the treatment benefit of talazoparib,” Litton said.

Investigators observed a statistically significant improvement in the estimated change in baseline global health status/QoL in patients treated with talazoparib (2.1; 95% CI, 0.1-4.1) compared with chemotherapy (—5.7; 95% CI, –10.0 to –1.4).

“Compared with chemotherapy, treatment with talazoparib was associated with a significant delay in the time to definitive clinically meaningful deterioration in the quality of life scores,” Litton said.

Furthermore, talazoparib was well tolerated. Approximately 35% of patients in the experimental arm experienced serious adverse events (AEs) compared with 31.0% in the chemotherapy arm. Patients in the 2 arms experienced similar rates of serious and drug-related AEs and grade 3/4 serious AEs. Investigators found that those assigned to talazoparib were less likely to experience AEs resulting in permanent drug discontinuation versus those assigned to chemotherapy (7.7% vs 9.5%, respectively).

Treatment with talazoparib (Talzenna) did not demonstrate a statistically significant overall survival (OS) benefit in patients with BRCA1/2-mutated metastatic HER2-negative breast cancer, according to updated findings from the phase 3 EMBRACA trial (NCT01945775).1 However, lead author Jennifer Litton, MD, said that there is still reason to believe treatment with the PARP inhibitor can improve OS.
 

Jason Harris