Research Spotlight

Witkowski, P., Philipson, L., Kaufman, D.B., Ratner, L., Abouljoud, M.S., Bellin, M., Buse, J., Kandeel, F., Stock, P., Mulligan, D., Markmann, J.F., Kozlowski, T., Andreoni, K., Alejandro, R., Baidal, D., Hardy, M.A., Wickrema, A., Mirmira, R.G., Fung, J., Becker, Y., Josephson, M.A., Bachul, P.J., Pyda, J.S., Charlton, M., Millis, J.M., Gaglia, J., Stratta, R.J., Fridell, J.A., Niederhaus, S., Forbes, R.C., Jayant, K., Robertson, R.P., Odorico, J., Levy, M., Harland, R., Abrams, P.L., Olaitan, O.K., Kandaswamy, R., Wellen, J., Japour, A.J., Desai, C.S., Naziruddin, B., Balamurugan, A.N., Barth, R.N. and Ricordi, C. (2020). “The Demise of Islet Allotransplantation in the US: A Call for an Urgent Regulatory Update The “ISLETS FOR US” Collaborative.” Am J Transplant Nov 29. [Epub ahead of print.].

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Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and “more than minimally manipulated” human cell and tissue products (HCT/Ps). Across the world, human islets are appropriately defined as “minimally manipulated tissue” which has led to islet transplantation becoming a standard-of-care procedure for patients with type 1 diabetes mellitus and problematic hypoglycemia. As a result of the outdated US regulations, only eleven patients underwent allo-ITx in the US between 2011-2016 and all in the setting of a clinical trial. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both, better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Nadler, E., Arondekar, B., Aguilar, K.M., Zhou, J., Chang, J., Zhang, X. and Pawar, V. (2020). “Treatment patterns and clinical outcomes in patients with advanced non-small cell lung cancer initiating first-line treatment in the US community oncology setting: a real-world retrospective observational study.” J Cancer Res Clin Oncol Dec 2. [Epub ahead of print.].

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PURPOSE: Treatments for advanced non-small cell lung cancer (NSCLC) have evolved to include targeted and immuno-oncology therapies, which have demonstrated clinical benefits in clinical trials. However, few real-world studies have evaluated these treatments in the first-line setting. METHODS: Adult patients with advanced NSCLC who initiated first-line treatment with chemotherapy, targeted therapies (TT), or immuno-oncology-based regimens in the US Oncology Network (USON) between March 1, 2015, and August 1, 2018, were included and followed up through February 1, 2019. Data were sourced from structured fields of USON electronic health records. Patient and treatment characteristics were assessed descriptively, with Kaplan-Meier methods used to evaluate time-to-event outcomes, including time to treatment discontinuation (TTD) and overall survival (OS). Adjusted Cox regression analyses and inverse probability of treatment weighting (IPTW) were performed to control for covariates that may have affected treatment selection and outcomes. RESULTS: Of 7746 patients, 75.6% received first-line systemic chemotherapy, 11.7% received immuno-oncology monotherapies, 8.5% received TT, and 4.2% received immuno-oncology combination regimens. Patients who received immuno-oncology monotherapies had the longest median TTD (3.5 months; 95% confidence interval [CI], 2.8-4.2) and OS (19.9 months; 95% CI, 16.6-24.1). On the basis of multivariable Cox regression and IPTW, immuno-oncology monotherapy was associated with reduced risk of death and treatment discontinuation relative to other treatments. CONCLUSION: These results suggest that real-world outcomes in this community oncology setting improved with the introduction of immuno-oncology therapies. However, clinical benefits are limited in certain subgroups and tend to be reduced compared with clinical trial observations.

Grosicki, S., Simonova, M., Spicka, I., Pour, L., Kriachok, I., Gavriatopoulou, M., Pylypenko, H., Auner, H.W., Leleu, X., Doronin, V., Usenko, G., Bahlis, N.J., Hajek, R., Benjamin, R., Dolai, T.K., Sinha, D.K., Venner, C.P., Garg, M., Gironella, M., Jurczyszyn, A., Robak, P., Galli, M., Wallington-Beddoe, C., Radinoff, A., Salogub, G., Stevens, D.A., Basu, S., Liberati, A.M., Quach, H., Goranova-Marinova, V.S., Bila, J., Katodritou, E., Oliynyk, H., Korenkova, S., Kumar, J., Jagannath, S., Moreau, P., Levy, M., White, D., Gatt, M.E., Facon, T., Mateos, M.V., Cavo, M., Reece, D., Anderson, L.D., Jr., Saint-Martin, J.R., Jeha, J., Joshi, A.A., Chai, Y., Li, L., Peddagali, V., Arazy, M., Shah, J., Shacham, S., Kauffman, M.G., Dimopoulos, M.A., Richardson, P.G. and Delimpasi, S. (2020). “Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial.” Lancet 396(10262): 1563-1573.

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BACKGROUND: Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. METHODS: This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m(2) once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m(2) twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. FINDINGS: Of 457 patients screened for eligibility, 402 were randomly allocated-195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group-and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2-19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4-19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73-not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11-10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53-0·93], p=0·0075). The most frequent grade 3-4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32-0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. INTERPRETATION: A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy.

Meyer, E.C., Zimering, R.T., Knight, J., Morissette, S.B., Kamholz, B.W., Coe, E., Carpenter, T.P., Keane, T.M., Kimbrel, N.A. and Gulliver, S.B. (2020). “Negative Emotionality Interacts with Trauma Exposure to Prospectively Predict Posttraumatic Stress Disorder Symptoms During Firefighters’ First 3 Years of Service.” J Trauma Stress Nov 28. [Epub ahead of print.].

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Firefighters (FFs) protect the public despite significant risks to their health and well-being stemming from frequent trauma exposure and other occupational stressors. A minority of FFs develop posttraumatic stress disorder (PTSD) or related mental health problems, whereas most remain remarkably resilient despite enormous stress. This points toward substantial variability in responses to traumatic stress among FFs. Personality, particularly negative emotionality (NEM), has been shown to predict the development of PTSD in other trauma-exposed populations, yet has not been prospectively studied in relation to PTSD in FFs. The aim of this secondary analysis from a broader study of mental health in FFs was to test whether preemployment NEM predicted PTSD symptom severity over time by influencing how FFs respond to traumatic experiences. In this first prospective study of the development of PTSD symptoms in professional FFs, 322 FFs were recruited from seven urban fire academies across the United States and followed over their first 3 years of fire service. We assessed NEM during the fire academy as well as trauma exposure and both self-reported and clinician-rated PTSD symptoms at 1-, 2-, and 3-year follow-ups. Level of trauma exposure and NEM predicted PTSD symptoms over time, and NEM moderated the effect of trauma exposure on clinician-rated PTSD symptoms across both trauma exposure measures at 1- and 3-year follow-ups, f(2) = .03-.10, but not at 2-year follow-up nor for self-reported PTSD symptoms. These findings indicate that NEM, assessed upon entry into a high-risk occupation, is useful in predicting PTSD symptom development.

Afzal, A.M. and Meyer, D.M. (2020). “The Dark Side of Chasing the Perfect Donor. Is It Time for Us to Change Cardiac Transplant Program Performance Metrics?” Transplantation Nov 9. [Epub ahead of print.].

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We read with great interest the manuscript by Butts et al on the topic of outcomes in pediatric heart transplantation in relation to center donor refusal rate. We applaud the authors for shedding light on this important topic of high donor refusal rate and its implications on waitlist mortality. The United States and Europe have a large proportion of donor hearts that are discarded in both adult and pediatric populations despite having a long waitlist. As the authors mentioned, 40% of pediatric heart donors in the US are discarded while still having a high waitlist mortality. Increasing access to solid organs and ultimately reducing waitlist mortality has been a topic of debate of the last several decades. [No abstract; except from article].