Research Spotlight

Sawinski, D., Mehta, S., Alhamad, T., Bromberg, J.S., Fischbach, B., Aeschbacher, T., Ghosh, S., Shekhtman, G., Dholakia, S., Brennan, D.C., Poggio, E., Bloom, R. and Jordan, S.C. (2021). “Association between dd-cfDNA levels, de novo donor specific antibodies, and eGFR decline: An analysis of the DART cohort.” Clin Transplant Jun 28. [Epub ahead of print].

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Despite advances in immunosuppression, long-term allograft survival remains a challenge and evidence of immune mediated injury can be detected even early in the posttransplant course. The emergence of de novo donor specific antibodies (dnDSA) is a particularly poor prognostic indicator; the detection of DSA is highly correlated with the development of antibody-mediated allograft injury and subsequent graft loss. A study from Wiebe et al. demonstrated that patients with dnDSA had markedly reduced 10-year allograft survival (57% versus 96%). One of the challenges in this population is the lack of consensus regarding therapeutic interventions for dnDSA, complicated by the fact that allograft dysfunction often progresses despite augmented immunosuppression. Particularly problematic is that long-lived plasma cells, the source of dnDSA, are generally resistant to maintenance immunosuppression, and therapies targeted towards them have significant side effects. [No abstract; excerpt from article].

Sanchez, L., Leleu, X., Beaumont, J.L., Yu, H., Hudgens, S., Simonova, M., Auner, H.W., Quach, H., Delimpasi, S., Špička, I., Pour, L., Kriachok, I., Dimopoulos, M.A., Usenko, G., Hájek, R., Benjamin, R., Sinha, D.K., Venner, C., Illmer, T., Garg, M.K., Stevens, D.A., Jagannath, S., Levy, M., Anderson, L.D., Jr., Bahlis, N.J., Facon, T., Cavo, M., Chai, Y., Ma, X., Tang, S., Leong, H., Shah, J., Shacham, S., Kauffman, M., Richardson, P. and Grosicki, S. (2021). “Peripheral Neuropathy Symptoms, Pain, and Functioning in Previously Treated Multiple Myeloma Patients Treated with Selinexor, Bortezomib, and Dexamethasone.” Am J Hematol Jun 23. [Epub ahead of print].

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With over 34 000 new cases and ~12 400 deaths from multiple myeloma (MM) anticipated in 2021 in the United States1 and about twice as many in Europe, there is an unmet medical need for therapies in patients with previously treated MM that have progressed on available agents. Currently, there are few agents with new mechanisms of action approved for early-line treatment. Selinexor (XPOVIO, Karyopharm Therapeutics Inc.) is a potent, oral, first-in-class, selective inhibitor of nuclear export that specifically blocks exportin 1 (XPO1). [No abstract; excerpt from article].

Saif, M.W., Becerra, C.R., Fakih, M.G., Sun, W., Popovic, L., Krishnamurthi, S., George, T.J., Rudek, M.A., Shepard, D.R., Skopek, J., Sramek, V., Zaric, B., Yamamiya, I., Benhadji, K.A., Hamada, K., He, Y. and Rosen, L. (2021). “A phase I, open-label study evaluating the safety and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and varying degrees of renal impairment.” Cancer Chemother Pharmacol Jun 7. [Epub ahead of print].

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PURPOSE: Trifluridine/tipiracil (FTD/TPI) is approved for advanced colorectal and gastric/gastroesophageal cancer; however, data in patients with renal impairment (RI) are limited. This phase I study evaluated FTD/TPI in patients with advanced solid tumors and varying degrees of RI to develop dosing guidance. METHODS: Patients were enrolled into normal renal function (CrCl ≥ 90 mL/min), mild RI (CrCl 60-89 mL/min), or moderate RI (CrCl 30-59 mL/min) cohorts and administered the recommended FTD/TPI dose (35 mg/m(2) twice daily, days 1-5 and 8-12; 28-day cycle). Based on interim pharmacokinetics/safety data, patients with severe RI (CrCl 15-29 mL/min) were enrolled and received FTD/TPI 20 mg/m(2) twice daily. RESULTS: Forty-three patients (normal renal function [n = 12]; mild RI [n = 12]; moderate RI [n = 11]; severe RI [n = 8]) were enrolled and treated. At steady state, compared to values in patients with normal renal function, FTD area under the curve (AUC) was not significantly different in patients with RI, but TPI AUC was significantly higher and increased with RI severity. FTD/TPI safety profile was consistent with prior experience, but grade ≥ 3 adverse events (AEs) were more frequent in the RI cohorts (83.3% [mild], 90.9% [moderate], 75.0% [severe], and normal [50.0%]). Hematologic AEs (anemia and neutropenia) were more frequent with RI. Overall, seven patients discontinued because of unrelated, nonhematologic AEs. CONCLUSION: FTD/TPI is safe and tolerable at the recommended 35 mg/m(2) dose in patients with mild/moderate RI and at the reduced 20 mg/m(2) dose in patients with severe RI.

Rolle, C.P., Berhe, M., Singh, T., Ortiz, R., Wurapa, A., Ramgopal, M., Leone, P.A., Matthews, J.E., Dalessandro, M., Underwood, M.R., Angelis, K., Wynne, B.R., Merrill, D., Nguyen, C., van Wyk, J. and Zolopa, A.R. (2021). “Dolutegravir/lamivudine as a first-line regimen in a test-and-treat setting for newly diagnosed people living with HIV.” Aids Jun 9. [Epub ahead of print].

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OBJECTIVES: Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. DESIGN: The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. METHODS: Eligible adults initiated DTG/3TC ≤14 days after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance <30 mL/min/1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA < 50 copies/mL at Week 24, regardless of antiretroviral regimen, among (1) all participants (intention-to-treat-exposed) and (2) those with available HIV-1 RNA data (observed). RESULTS: Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in 8 participants (5 with HBV co-infection, 1 with baseline M184 V, 1 for adverse event [AE; rash], 1 participant decision). At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA < 50 copies/mL. Incidence of drug-related AEs was low (7%); no drug-related serious AEs occurred. CONCLUSIONS: These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed

Quinn, L., Riley, N., Tyrell, C.M., Judd, D., Gill-Body, K.M., Hedman, L.D., Packel, A., Brown, D.A., Nabar, N. and Scheets, P. (2021). “A Framework for Movement Analysis of Tasks: Recommendations from the Academy of Neurologic Physical Therapy’s Movement System Task Force.” Phys Ther Jun 21;pzab154. [Epub ahead of print].

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The American Physical Therapy Association’s Vision Statement of 2013 asserts that physical therapists optimize movement in order to improve the human experience. In accordance with this vision, physical therapists strive to be recognized as experts in movement analysis. However, there continues to be no accepted method to conduct movement analysis, nor an agreement of key terminology to describe movement observations. As a result, the Academy of Neurologic Physical Therapy organized a Task Force that was charged with advancing the state of practice with respect to these issues, including the development of a proposed method for movement analysis of tasks. This paper presents the work of the Task Force, which includes: 1) development of a method for conducting movement analysis within the context of the movement continuum during 6 core tasks (sitting, sit to stand, standing, walking, step up/down, and reach/grasp/manipulate); 2) glossary of movement constructs that can provide a common language for movement analysis across a range of tasks: symmetry, speed, amplitude, alignment, verticality, stability, smoothness, sequencing, timing, accuracy and symptom provocation; and 3) recommendations for task and environmental variations that can be systematically applied. The expectation is that this systematic framework and accompanying terminology will be easily adapted to additional patient or client-specific tasks, contribute to development of movement system diagnostic labels, and ultimately improve consistency across patient/client examination, evaluation, and intervention for the physical therapy profession. Next steps should include validation of this framework across patient/client groups and settings.